Ire1 small molecule inhibitors

ABSTRACT

Provided herein are small molecule inhibitors for the targeting or IRE1 protein family members. Binding may be direct or indirect. Further provided herein are methods of using IRE1 small molecule inhibitors for use in treating or ameliorating cancer in a subject. Moreover, IRE1 small molecule inhibitors described herein are for the treatment of cancer, where the cancer is a solid or hematologic cancer.

CROSS-REFERENCE

This application claims benefit of U.S. Provisional Patent ApplicationNo. 62/513,929 filed on Jun. 1, 2017, which is incorporated herein byreference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on May 23, 2018, isnamed 51089-711_201_SL.txt and is 23,840 bytes in size.

BACKGROUND

Aggressive tumors have evolved strategies that enable them to thriveunder constant adverse conditions. For example, cancer cells respond tohypoxia, nutrient starvation, oxidative stress, and high metabolicdemand by adjusting their protein folding capacity via the endoplasmicreticulum (ER) stress response pathway. There exists a need for improvedmethods and compositions to target cancer cells and counter theirmechanisms of survival.

BRIEF SUMMARY

Provided in one aspect is a compound of Formula (I), or apharmaceutically acceptable salt, or solvate thereof:

wherein,

is a substituted C₃-C₁₀ cycloalkyl that is substituted with 1-3R¹ and0-3R²;

-   each R¹ is independently —OR⁶, —SR⁶, —S(═O)R⁷, —S(═O)₂R⁷, or    —N(R⁶)₂;-   each R² is independently H, halogen, —CN, —OR⁸, —SR, —S(═O)R⁹,    —S(═O)₂R⁹, —S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂R⁹, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R⁸,    —OCO₂R⁹, —N(R⁸)₂, —OC(═O)N(R⁸)₂, —NR C(═O)R⁹, —NR⁸C(═O)OR⁹,    optionally substituted C₁-C₄alkyl, optionally substituted    C₁-C₄fluoroalkyl, optionally substituted C₁-C₄heteroalkyl,    optionally substituted C₃-C₆cycloalkyl, optionally substituted aryl,    or optionally substituted heteroaryl;-   each R⁶ is independently H, optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄heteroalkyl, optionally substituted    C₁-C₄fluoroalkyl, —X-optionally substituted C₁-C₄alkyl,    —X-optionally substituted C₁-C₄heteroalkyl, —X-optionally    substituted C₁-C₄fluoroalkyl, optionally substituted    C₃-C₆cycloalkyl, optionally substituted C₂-C₁₀heterocycloalkyl,    optionally substituted aryl, or optionally substituted heteroaryl;-   or two R⁶ are taken together with the N atom to which they are    attached to form an optionally substituted heterocycle;-   X is —(C═O)—;-   each R⁷ is independently optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄heteroalkyl, optionally substituted    C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl, optionally    substituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl;-   each R⁸ is independently H, optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄heteroalkyl, optionally substituted    C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl, optionally    substituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl;-   or two R⁸ are taken together with the N atom to which they are    attached to form an optionally substituted heterocycle;-   each R⁹ is independently optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄heteroalkyl, or optionally substituted    C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl, optionally    substituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl;-   A² is N or CR^(A);-   R^(A), R^(A1), R^(A2), and R^(A3) are each independently H, halogen,    optionally substituted C₁-C₄alkyl, optionally substituted    C₁-C₄fluoroalkyl, optionally substituted aryl, or —OR¹⁰;-   R¹⁰ is independently H, optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄fluoroalkyl, optionally substituted    C₁-C₄heteroalkyl, optionally substituted C₃-C₆cycloalkyl, optionally    substituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl;-   ring A is a monocyclic carbocycle or a monocyclic heterocycle;-   each R³ is independently H, halogen, —CN, —OR¹¹, —SR¹¹, —N(R¹¹)₂,    optionally substituted C₁-C₄alkyl, optionally substituted    C₁-C₄fluoroalkyl, optionally substituted C₁-C₄heteroalkyl,    optionally substituted C₃-C₆cycloalkyl, optionally substituted    C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or optionally    substituted heteroaryl;-   each R¹¹ is independently H, optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄fluoroalkyl, optionally substituted    C₁-C₄heteroalkyl, optionally substituted C₃-C₆cycloalkyl, optionally    substituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl;-   n is 0, 1, 2, 3, or 4;-   R⁴ and R⁵ are each independently H, halogen, —CN, —OR¹², —SR¹²,    —N(R¹²)₂, optionally substituted C₁-C₄alkyl, optionally substituted    C₁-C₄fluoroalkyl, optionally substituted C₁-C₄heteroalkyl,    optionally substituted C₃-C₆cycloalkyl, optionally substituted    C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or optionally    substituted heteroaryl; and-   R¹² is independently H, optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄fluoroalkyl, optionally substituted    C₁-C₄heteroalkyl, optionally substituted C₃-C₆cycloalkyl, optionally    substituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl.

In some embodiments,

is substituted C₄-C₇ cycloalkyl that is substituted with 1-3R¹ and0-3R².

In some embodiments

and

q is 0, 1, 2, or 3.

In some embodiments,

and

-   -   q is 0, 1, 2, or 3.

In some embodiments,

and

-   -   q is 0, 1, 2, or 3.

In some embodiments, q is 0 or 1. In some embodiments, each R⁶ isindependently H, optionally substituted C₁-C₄alkyl, optionallysubstituted C₁-C₄heteroalkyl, optionally substituted C₁-C₄fluoroalkyl,—X-optionally substituted C₁-C₄alkyl, —X-optionally substitutedC₁-C₄heteroalkyl, or —X-optionally substituted C₁-C₄fluoroalkyl. In someembodiments, each R⁶ is independently H. In some embodiments, each R² isindependently H, optionally substituted C₁-C₄alkyl, optionallysubstituted C₁-C₄heteroalkyl, or optionally substitutedC₁-C₄fluoroalkyl.

In some embodiments

R⁶ is H, optionally substituted C₁-C₄alkyl, optionally substitutedC₁-C₄heteroalkyl, optionally substituted C₁-C₄fluoroalkyl, —X-optionallysubstituted C₁-C₄alkyl, —X-optionally substituted C₁-C₄heteroalkyl, or—X-optionally substituted C₁-C₄fluoroalkyl; q is 0 or 1; and R² is H,optionally substituted C₁-C₄alkyl, optionally substitutedC₁-C₄heteroalkyl, or optionally substituted C₁-C₄fluoroalkyl.

In some embodiments, R⁶ is H. In some embodiments, A² is N. In someembodiments, A² is CR^(A). In some embodiments, R^(A) is H, optionallysubstituted C₁-C₄alkyl, or optionally substituted C₁-C₄fluoroalkyl. Insome embodiments, R^(A) is H. In some embodiments, R^(A1) is H,optionally substituted C₁-C₄alkyl, or optionally substitutedC₁-C₄fluoroalkyl. In some embodiments, R^(A1) is H. In some embodiments,R^(A2) is H, optionally substituted C₁-C₄alkyl, or optionallysubstituted C₁-C₄fluoroalkyl. In some embodiments, R^(A2) is H. In someembodiments, R^(A3) is H, halogen, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄fluoroalkyl, optionally substituted aryl, or—OR¹⁰. In some embodiments, R^(A3) is H, halogen, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄fluoroalkyl, or —OR¹⁰. In someembodiments, R^(A3) is optionally substituted C₁-C₄alkyl. In someembodiments, R^(A3) is methyl, ethyl, propyl or butyl. In someembodiments, R^(A3) is —OR¹⁰ and R¹⁰ is methyl, ethyl, propyl or butyl.In some embodiments, ring A is phenylene or a monocyclicC₃-C₈cycloalkylene that is selected from cyclopropylene, cyclobutylene,cyclopentylene, cyclohexylene, cycloheptylene, and cyclooctylene. Insome embodiments, ring A is phenylene.

In some embodiments,

In some embodiments, ring A is a monocyclic C₁-C₈heteroarylenecontaining 1-4 N atoms, and 0 or 1 O or S atom, or a monocyclicC₁-C₅heteroarylene containing 0-4 N atoms, and 1 O or S atom. In someembodiments, ring A is a monocyclic 6-membered heteroarylene selectedfrom pyridinylene, pyrimidinylene, pyrazinylene, and pyridazinylene. Insome embodiments, ring A is pyridinylene.

In some embodiments,

In some embodiments,

In some embodiments, ring A is a monocyclic 5-membered heteroaryleneselected from furanylene, thienylene, pyrrolylene, oxazolylene,thiazolylene, imidazolylene, pyrazolylene, triazolylene, tetrazolylene,isoxazolylene, isothiazolylene, oxadiazolylene, and thiadiazolylene. Insome embodiments, ring A is oxazolylene, thiazolylene, imidazolylene,pyrazolylene, or oxadiazolylene. In some embodiments, ring A ispyrazolylene.

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, ring A is a ring A is a monocyclicC₂-C₈heterocycloalkylene containing at least 1 N atom in the ring thatis selected from aziridinylene, azetidinylene, pyrrolidinylene,piperidinylene, piperazinylene, and azepanylene. In some embodiments,each R³ is independently H, halogen, —CN, —OR¹¹, —SR¹¹, optionallysubstituted C₁-C₄alkyl, or optionally substituted C₁-C₄fluoroalkyl; andn is 1, 2, or 3. In some embodiments, R³ is optionally substitutedC₁-C₄alkyl.

In some embodiments, R³ is methyl, ethyl, propyl, or butyl. In someembodiments, R³ is —OR¹¹. In some embodiments, R¹¹ is H, optionallysubstituted C₁-C₄alkyl, or optionally substituted C₁-C₄fluoroalkyl. Insome embodiments, R¹¹ is methyl, ethyl, propyl, or butyl. In someembodiments, R¹¹ is —CF₃ or —CH₂CF₃. In some embodiments, R⁴ is H,halogen, —CN, —OR¹², —SR¹², —N(R¹²)₂, optionally substituted C₁-C₄alkyl,or optionally substituted C₁-C₄fluoroalkyl. In some embodiments, R⁴ isH. In some embodiments, R⁴ is halogen. In some embodiments, R⁴ is —Cl,—Br, —F, or —I. In some embodiments, R⁴ is —OR¹². In some embodiments,R¹² is H, optionally substituted C₁-C₄alkyl, or optionally substitutedC₁-C₄fluoroalkyl. In some embodiments, R⁴ is optionally substitutedC₁-C₄alkyl. In some embodiments, R⁴ is methyl, ethyl, propyl, or butyl.In some embodiments, R⁴ is optionally substituted C₁-C₄fluoroalkyl. Insome embodiments, R⁴ is —CF₃ or —CH₂CF₃. In some embodiments, R⁵ is H,halogen, —CN, —OR¹², —SR¹², —N(R¹²)₂, optionally substituted C₁-C₄alkyl,or optionally substituted C₁-C₄fluoroalkyl. In some embodiments, R⁵ isH. In some embodiments, R⁵ is halogen. In some embodiments, R⁵ is —Cl,—Br, —F, or —I. In some embodiments, R⁵ is —OR¹². In some embodiments,R¹² is H, optionally substituted C₁-C₄alkyl, or optionally substitutedC₁-C₄fluoroalkyl. In some embodiments, R⁵ is optionally substitutedC₁-C₄alkyl. In some embodiments, R⁵ is methyl, ethyl, propyl, or butyl.In some embodiments, R⁵ is optionally substituted C₁-C₄fluoroalkyl. Insome embodiments, R⁵ is —CF₃ or —CH₂CF₃.

In some embodiments, the compound has the structure of formula (Ia)

In some embodiments, the compound has the structure of formula (Ib)

In some embodiments, the compound has the structure of formula (Ic)

In some embodiments,

andq is 0 or 1.

In some embodiments, each R⁶ is independently H, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄heteroalkyl, optionallysubstituted C₁-C₄fluoroalkyl, —X-optionally substituted C₁-C₄alkyl,—X-optionally substituted C₁-C₄heteroalkyl, or —X-optionally substitutedC₁-C₄fluoroalkyl. In some embodiments, each R⁶ is independently H. Insome embodiments, each R² is independently H, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄heteroalkyl, or optionallysubstituted C₁-C₄fluoroalkyl. In some embodiments, A² is N. In someembodiments, A² is CR^(A). In some embodiments, R^(A) is H, optionallysubstituted C₁-C₄alkyl, or optionally substituted C₁-C₄fluoroalkyl. Insome embodiments, R^(A) is H. In some embodiments, R^(A1) is H,optionally substituted C₁-C₄alkyl, or optionally substitutedC₁-C₄fluoroalkyl. In some embodiments, R^(A1) is H. In some embodiments,R^(A2) is H, optionally substituted C₁-C₄alkyl, or optionallysubstituted C₁-C₄fluoroalkyl. In some embodiments, R^(A2) is H. In someembodiments, R^(A3) is H, halogen, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄fluoroalkyl, optionally substituted aryl, or—OR¹⁰. In some embodiments, R^(A3) is H, halogen, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄fluoroalkyl, or —OR¹⁰. In someembodiments, R^(A3) is optionally substituted C₁-C₄alkyl. In someembodiments, R^(A3) is methyl, ethyl, propyl, or butyl. In someembodiments, R^(A3) is ethyl. In some embodiments, ring A is phenylene.In some embodiments, ring A is a monocyclic 6-membered heteroaryleneselected from pyridinylene, pyrimidinylene, pyrazinylene, andpyridazinylene. In some embodiments, ring A is pyridinylene. In someembodiments, ring A is a monocyclic 5-membered heteroarylene selectedfrom furanylene, thienylene, pyrrolylene, oxazolylene, thiazolylene,imidazolylene, pyrazolylene, triazolylene, tetrazolylene, isoxazolylene,isothiazolylene, oxadiazolylene, and thiadiazolylene. In someembodiments, ring A is pyrazolylene. In some embodiments, each R³ isindependently H, —OR¹¹, optionally substituted C₁-C₄alkyl, or optionallysubstituted C₁-C₄fluoroalkyl; and n is 1, 2, or 3. In some embodiments,R¹¹ is H, optionally substituted C₁-C₄alkyl, or optionally substitutedC₁-C₄fluoroalkyl. In some embodiments, R⁴ and R⁵ are each independentlyH, halogen, —CN, —OR¹², —SR¹², —N(R¹²)₂, optionally substitutedC₁-C₄alkyl, or optionally substituted C₁-C₄fluoroalkyl.

In some embodiments, the compound has the structure of formula (Id)

and R^(A3) is optionally substituted C₁-C₄ alkyl.

In some embodiments, the compound has the structure of formula (Ie)

In some embodiments, the compound has the structure of formula (If)

In some embodiments, ring A is phenylene, pyridinylene, pyrazolylene,thiazolylene, imidazolylene, oxazolylene, or oxadiazolylene. In someembodiments, R⁴ and R⁵ are each independently H, halogen, —CN, —OR¹²,—SR¹², —N(R¹²)₂, optionally substituted C₁-C₄alkyl, or optionallysubstituted C₁-C₄fluoroalkyl.

In another aspect, provided herein is a compound, or a pharmaceuticallyacceptable salt, or solvate thereof, selected from:

-   N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-ethylpyridazin-3-yl)-2-chlorobenzenesulfonamide;-   2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-hydroxycyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-cyanobenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-methylquinazolin-6-yl)-6-ethylpyridin-2-yl)-2-chlorobenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-methylquinazolin-6-yl)-6-methylpyridin-2-yl)-2-chlorobenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-(trifluoromethoxy)pyridin-2-yl)-2-chlorobenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methoxybenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-2-methylbenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-3-methylbenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-5-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;-   2-chloro-N-(4-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluoro-5-methoxyphenyl)benzenesulfonamide;-   2-chloro-N-(4-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-2-fluoro-5-methoxyphenyl)benzenesulfonamide;-   N-(5-(2-(((1    r,4r)-4-aminocyclohexyl)amino)-8-(1,1-difluoroethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-(methoxymethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;-   N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-(trifluoromethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;-   2-chloro-N-(5-(2-((4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)amino)-8-ethylquinazolin-6-yl)-6-ethylpyridin-2-yl)benzenesulfonamide;-   N-(5-(2-(((1s,4s)-4-aminocyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;-   N-(5-(2-(((1s,4s)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;    and-   N-(5-(2-(((1s,4s)-4-aminocyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide.

In some embodiments, the compound or pharmaceutically acceptable salt,or solvate thereof, selectively binds to IRE1a at one or more bindingsites. In some embodiments, the IRE1a comprises an RNase domain, akinase domain, or any combination thereof. In some embodiments, thekinase domain is an auto-transphosphorylation kinase domain. In someembodiments, the kinase domain comprises an ATP-binding pocket. In someembodiments, the kinase domain comprises an activation loop. In someembodiments, at least one binding site is within the RNase domain. Insome embodiments, at least one binding site is within the kinase domain.In some embodiments, the at least one binding site is within theATP-binding pocket of the kinase domain. In some embodiments, In someembodiments, the at least one binding site is within the activation loopof the kinase domain. In some embodiments, binding occurs at a firstbinding site. In some embodiments, the first binding site is locatedwithin the RNase domain, kinase domain, ATP-binding pocket, oractivation loop. In some embodiments, the first binding site comprisesat least one amino acid residue of within amino acid residues 465-977 ofSEQ ID NO: 1. In some embodiments, the first binding site comprises atleast one amino acid residue within amino acid residues 568-833 of SEQID NO: 1. In some embodiments, the first binding site comprises at leastone amino acid residue within amino acid residues 577-586, 597, 599,626, 642-643, 645, 648, 688, 692-693, 695, or 711 of SEQ ID NO: 1. Insome embodiments, the first binding site comprises at least one aminoacid residue within amino acid residues 710-725 or 729-736 of SEQ IDNO: 1. In some embodiments, the first binding site comprises at leastone amino acid residue within amino acid residues 835-963 of SEQ IDNO: 1. In some embodiments, binding further occurs at a second bindingsite. In some embodiments, the second binding site is located within theRNase domain, the kinase domain, the ATP-binding pocket, or theactivation loop. In some embodiments, the second binding site comprisesat least one amino acid residue of within amino acid residues 465-977 ofSEQ ID NO: 1. In some embodiments, the second binding site comprises atleast one amino acid residue within amino acid residues 568-833 of SEQID NO: 1. In some embodiments, the second binding site comprises atleast one amino acid residue within amino acid residues 577-586, 597,599, 626, 642-643, 645, 648, 688, 692-693, 695, or 711 of SEQ ID NO: 1.In some embodiments, the second binding site comprises at least oneamino acid residue within amino acid residues 710-725 or 729-736 of SEQID NO: 1. In some embodiments, the second binding site comprises atleast one amino acid residue within amino acid residues 835-963 of SEQID NO: 1. In some embodiments, binding occurs when the IRE1a is in ahomo-dimerized conformation. In some embodiments, binding occurs whenthe IRE1a is in an oligomerized conformation. In some embodiments,binding occurs when the IRE1a is in a non-oligomerized or non-dimerizedconformation. In some embodiments, binding occurs when the IRE1a is inan ATP-bound state. In some embodiments, binding occurs when the IRE1ais in a non-ATP-bound state. In some embodiments, the compoundselectively binds to a first IRE1a. In some embodiments, selectivelybinding to the first IRE1a blocks dimerization of the first IRE1a to asecond IRE1a. In some embodiments, selectively binding to the firstIRE1a blocks auto-transphosphorylation of the first IRE1a. In someembodiments, selectively binding to the first IRE1a blocksauto-transphosphorylation of a second IRE1a to which the first IRE1a isdimerized. In some embodiments, selectively binding to the first IRE1ablocks activation of the first IRE1a. In some embodiments, selectivelybinding to the first IRE1a blocks activation a second IRE1a to which thefirst IRE1a is dimerized. In some embodiments, selectively binding tothe first IRE1a blocks kinase activity of the first IRE1a. In someembodiments, selectively binding to the first IRE1a blocks kinaseactivity of a second IRE1a to which the first IRE1a is dimerized. Insome embodiments, selectively binding to the first IRE1a blocks RNaseactivity of the first IRE1a. In some embodiments, selectively binding tothe first IRE1a blocks RNase activity of a second IRE1a to which thefirst IRE1a is dimerized.

In another aspect, provided herein is a compound that selectively bindsa first IRE1a at two or more sites, wherein when the compound is boundto the first IRE1a protein, the compound binds to an ATP-binding pocketof the first IRE1a and blocks the binding of ATP to the first IRE1a. Insome embodiments, the ATP binding pocket is comprised within a kinasedomain. In some embodiments, the ATP binding pocket is comprised withinamino acid residues 465-977 of SEQ ID NO: 1. In some embodiments, theATP binding pocket is comprised within amino acid residues 568-833 ofSEQ ID NO: 1. In some embodiments, the ATP binding pocket comprises oneor more of amino acid resides 577-586, 597, 599, 626, 642-643, 645, 648,688, 692-693, 695, or 711 of SEQ ID NO: 1.

In another aspect, provided herein is a pharmaceutical compositioncomprising any one of the compounds described herein, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition further comprises one ormore pharmaceutically acceptable excipients.

In another aspect, provided herein is a method for treating orameliorating the effects of a disease associated with altered IRE1signaling, the method comprising administering to a subject in needthereof a pharmaceutical composition, wherein the pharmaceuticalcomposition comprises the compound of any one of the compounds describedherein. In some embodiments, the disease is cancer. In some embodiments,the cancer is a solid cancer or a hematologic cancer. In someembodiments, the cancer is ovarian cancer, breast cancer, or triplenegative breast cancer (TNBC).

In another aspect, provided herein is a method for treating orameliorating a cell proliferative disorder, the method comprisingadministering a pharmaceutical composition comprising a compound, or apharmaceutically acceptable salt, or solvate thereof, that selectivelybinds to at least one amino acid residue of a IRE1 family proteincomprising an RNase domain and kinase domain. In some embodiments, theIRE1 family protein is IRE1a. In some embodiments, the compound binds toan ATP-binding site of IRE1a. In some embodiments, the cellproliferative disorder is cancer. In some embodiments, the cancer is asolid cancer or a hematologic cancer, lung cancer, or bladder cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims.

A better understanding of the features and advantages of the presentinvention will be obtained by reference to the following detaileddescription that sets forth illustrative embodiments, in which theprinciples of the invention are utilized, and the accompanying drawingsof which:

FIG. 1 shows an example diagram of the domain structure of IRE1a. Asignal peptide (P) and transmembrane (TM) region are indicated.

FIG. 2 shows an example alignment of the C-terminal half IRE1orthologues from yeast (ScIre1) (SEQ ID NO: 4), human (HsIre1) (SEQ IDNO: 5), mouse (MmIre1) (SEQ ID NO: 6), and rat (RnIRE1) (SEQ ID NO: 7).Stars indicate kinase domain dimer interface residues. Circles indicateKinase extension nuclease (KEN) domain dimer interface residues.Triangles indicate putative nuclease active site residues. Yellowhighlighted residues are highly conserved in Ire1 orthologues. Greenhighlighted residues are invariant in all analyzed Ire1 orthologues.Blue highlighted residues are invariant in analyzed RNaseL and Ire1orthologues.

FIG. 3 depicts the bioavailability of Compound 3 and Compound 37 invivo. Mice were dosed with Compound 3 or Compound 37 intravenously,orally, and intraperitoneally.

FIG. 4 shows suppression of IRE1a-dependent splicing of X-box bindingprotein 1 (XBP1). The bottom left panel shows the unspliced (XBP1u) andspliced XBP1(s) protein with varying combinations of Compound 3 and TM,where mpk is mg/kg.

FIG. 5 shows that Compound 3 can inhibit IRE1a-dependent signaling invarious cell types in the tumor microenvironment.

DETAILED DESCRIPTION Certain Terminology

Unless otherwise stated, the following terms used in this applicationhave the definitions given below. The use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl group, i.e., the alkyl group is selected from amongmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroup is branched or straight chain. In some embodiments, the “alkyl”group has 1 to 10 carbon atoms, i.e. a C₁-C₁₀alkyl. Whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbonatoms, 5 carbon atoms, 6 carbon atoms, etc., up to and including 10carbon atoms, although the present definition also covers the occurrenceof the term “alkyl” where no numerical range is designated. In someembodiments, an alkyl is a C₁-C₆alkyl. In one aspect the alkyl ismethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, ort-butyl. Typical alkyl groups include, but are in no way limited to,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiarybutyl, pentyl, neopentyl, or hexyl.

An “alkylene” group refers refers to a divalent alkyl radical. Any ofthe above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. In someembodiments, an alkelene is a C₁-C₆alkylene. In other embodiments, analkylene is a C₁-C₄alkylene. In certain embodiments, an alkylenecomprises one to four carbon atoms (e.g., C₁-C₄ alkylene). In otherembodiments, an alkylene comprises one to three carbon atoms (e.g.,C₁-C₃ alkylene). In other embodiments, an alkylene comprises one to twocarbon atoms (e.g., C₁-C₂ alkylene). In other embodiments, an alkylenecomprises one carbon atom (e.g., C₁ alkylene). In other embodiments, analkylene comprises two carbon atoms (e.g., C₂ alkylene). In otherembodiments, an alkylene comprises two to four carbon atoms (e.g., C₂-C₄alkylene).

Typical alkylene groups include, but are not limited to, —CH₂—,—CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, and the like.

The term “alkenyl” refers to a type of alkyl group in which at least onecarbon-carbon double bond is present. In one embodiment, an alkenylgroup has the formula —C(R)═CR₂, wherein R refers to the remainingportions of the alkenyl group, which may be the same or different. Insome embodiments, R is H or an alkyl. In some embodiments, an alkenyl isselected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl,pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenylgroup include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —C(CH₃)═CHCH₃, and—CH₂CH═CH₂.

The term “alkynyl” refers to a type of alkyl group in which at least onecarbon-carbon triple bond is present. In one embodiment, an alkenylgroup has the formula —C≡C—R, wherein R refers to the remaining portionsof the alkynyl group. In some embodiments, R is H or an alkyl.

In some embodiments, an alkynyl is selected from ethynyl, propynyl,butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of analkynyl group include —C≡CH, —C≡CCH₃—C≡CCH₂CH₃, —CH₂C≡CH.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where x is0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

The term “aromatic” refers to a planar ring having a delocalizedit-electron system containing 4n+2 t electrons, where n is an integer.The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g.,phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”)groups (e.g., pyridine). The term includes monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups.

The term “carbocyclic” or “carbocycle” refers to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from “heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atomwhich is different from carbon. In some embodiments, at least one of thetwo rings of a bicyclic carbocycle is aromatic. In some embodiments,both rings of a bicyclic carbocycle are aromatic. Carbocycle includescycloalkyl and aryl.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. In one aspect, aryl isphenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In someembodiments, an aryl is a C₆-C₁₀aryl. Depending on the structure, anaryl group is a monoradical or a diradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls arespirocyclic or bridged compounds. In some embodiments, cycloalkyls areoptionally fused with an aromatic ring, and the point of attachment isat a carbon that is not an aromatic ring carbon atom. In someembodiments, cycloalkyl groups include groups having from 3 to 10 ringatoms. In some embodiments, cycloalkyl groups include groups having from3 to 6 ring atoms. In some embodiments, cycloalkyl groups are selectedfrom among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl,norbornyl and bicycle[0.1.1.1]pentyl. In some embodiments, a cycloalkylis a C₃-C₆cycloalkyl. In some embodiments, a cycloalkyl is a monocycliccycloalkyl. Monocyclic cycloalkyls include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl,norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

The term “cycloalkylene” refers to a monocyclic or polycyclic aliphatic,non-aromatic divalent radical, wherein each of the atoms forming thering (i.e. skeletal atoms) is a carbon atom. In some embodiments,cycloalkylene are spirocyclic or bridged compounds. In some embodiments,cycloalkylenes are optionally fused with an aromatic ring, and the pointof attachment is at a carbon that is not an aromatic ring carbon atom.In some embodiments, cycloalkylene groups include groups having from 3to 10 ring atoms. In some embodiments, cycloalkylene groups includegroups having from 3 to 6 ring atoms.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, orbromo.

The term “haloalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a halogen atom. In one aspect, a fluoralkyl is aC₁-C₆fluoroalkyl.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is aC₁-C₆fluoroalkyl. In some embodiments, a fluoroalkyl is selected fromtrifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is aC₁-C₆heteroalkyl.

The term “heteroalkylene” refers to an alkylene group in which one ormore skeletal atoms of the alkylene are selected from an atom other thancarbon, e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, sulfur, orcombinations thereof. In some embodiments, a heteroalkylene is attachedto the rest of the molecule at a carbon atom of the heteroalkylene. Inone aspect, a heteroalkylene is a C₁-C₆heteroalkylene.

As used herein, the term “heteroatom” refers to an atom of any elementother than carbon or hydrogen. In some embodiments, the heteroatom isnitrogen, oxygen, or sulfur. In some embodiments, the heteroatom isnitrogen or oxygen. In some embodiments, the heteroatom is nitrogen.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings (also known asheteroalicyclic groups) containing one to four heteroatoms in thering(s), where each heteroatom in the ring(s) is selected from O, S andN, wherein each heterocyclic group has from 3 to 10 atoms in its ringsystem, and with the proviso that any ring does not contain two adjacentO or S atoms. In some embodiments, heterocycles are monocyclic,bicyclic, polycyclic, spirocyclic or bridged compounds. Non-aromaticheterocyclic groups (also known as heterocycloalkyls) include ringshaving 3 to 10 atoms in its ring system and aromatic heterocyclic groupsinclude rings having 5 to 10 atoms in its ring system. The heterocyclicgroups include benzo-fused ring systems. Examples of non-aromaticheterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl,indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl,3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups are either C-attached (or C-linked)or N-attached where such is possible. For instance, a group derived frompyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole includesimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles areoptionally substituted with one or two oxo (═O) moieties, such aspyrrolidin-2-one. In some embodiments, at least one of the two rings ofa bicyclic heterocycle is aromatic. In some embodiments, both rings of abicyclic heterocycle are aromatic.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groupsinclude monocyclic heteroaryls and bicyclcic heteroaryls. Monocyclicheteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine,indole, benzofuran, benzothiophene, indazole, benzimidazole, purine,quinolizine, quinoline, isoquinoline, cinnoline, phthalazine,quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In someembodiments, a heteroaryl contains 0-4 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 Satoms in the ring. In some embodiments, a heteroaryl contains 1-4 Natoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments,heteroaryl is a C₁-C₉heteroaryl. In some embodiments, monocyclicheteroaryl is a C₁-C₈heteroaryl. In some embodiments, monocyclicheteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, bicyclic heteroaryl is a C₆-C₉heteroaryl.

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkylgroup that includes at least one heteroatom selected from nitrogen,oxygen and sulfur. In some embodiments, a heterocycloalkyl is aspirocyclic or bridged compound. In some embodiments, a heterocycloalkylis fused with an aryl or heteroaryl. In some embodiments, theheterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl,pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, orthiazolidin-2-onyl. The term heteroalicyclic also includes all ringforms of the carbohydrates, including but not limited to themonosaccharides, the disaccharides and the oligosaccharides. In oneaspect, a heterocycloalkyl is a C₂-C₁₀heterocycloalkyl. In anotheraspect, a heterocycloalkyl is a C₄-C₁₀heterocycloalkyl. In someembodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. Insome embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atomsand 0-1 S atoms in the ring.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment or functional group of amolecule.

Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

The term “optionally substituted” or “substituted” means that thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from D, halogen, —CN,—NH₂, —NH(alkyl), —CH₂N(alkyl)₂, —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl,—CH₂NH₂, —C(═O)NH₂, —C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂,—S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl,heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl,aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide,alkylsulfone, and arylsulfone. In some other embodiments, optionalsubstituents are independently selected from D, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂(C₁-C₄alkyl), —CH₂NH₂, —C(═O)NH₂,—C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂, —S(═O)₂NH₂,—S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and—S(═O)₂C₁-C₄alkyl. In some embodiments, optional substituents areindependently selected from D, halogen, —CN, —NH₂, —OH, —NH(CH₃),—N(CH₃)₂, —CH₃, —CH₂CH₃, —CH₂NH₂, —CF₃, —OCH₃, and —OCF₃. In someembodiments, substituted groups are substituted with one or two of thepreceding groups. In some embodiments, an optional substituent on analiphatic carbon atom (acyclic or cyclic) includes oxo (═O).

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may, in certain embodiments, exist astautomers. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the pyrazolecompounds described herein is intended to encompass any and allpharmaceutically suitable salt forms. Preferred pharmaceuticallyacceptable salts of the compounds described herein are pharmaceuticallyacceptable acid addition salts and pharmaceutically acceptable baseaddition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like.

Also contemplated are salts of amino acids, such as arginates,gluconates, and galacturonates (see, for example, Berge S. M. et al.,“Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19(1997)). Acid addition salts of basic compounds may be prepared bycontacting the free base forms with a sufficient amount of the desiredacid to produce the salt according to methods and techniques with whicha skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds and the like.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, or combinations thereof. Insome embodiments, a modulator is an agonist.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds andcompositions described herein are administered orally.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered, which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is optionallydetermined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound described herein, or a pharmaceuticallyacceptable salt thereof, and a co-agent, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g. acompound described herein, or a pharmaceutically acceptable saltthereof, and a co-agent, are administered to a patient as separateentities either simultaneously, concurrently or sequentially with nospecific intervening time limits, wherein such administration provideseffective levels of the two compounds in the body of the patient. Thelatter also applies to cocktail therapy, e.g. the administration ofthree or more active ingredients.

The terms “kit” and “article of manufacture” are used as synonyms.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human.

As used herein, “treatment” or “treating” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

Compounds

Compounds described herein, including pharmaceutically acceptable salts,and pharmaceutically acceptable solvates thereof, that modulate IRE1mediated signaling, directly or indirectly.

Provided in one aspect is a compound of Formula (I), or apharmaceutically acceptable salt, or solvate thereof:

wherein,

is a substituted C₃-C₁₀ cycloalkyl that is substituted with 1-3R¹ and0-3R²;

-   each R¹ is independently —OR⁶, —SR⁶, —S(═O)R⁷, —S(═O)₂R⁷, or    —N(R⁶)₂;-   each R² is independently H, halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁹,    —S(═O)₂R⁹, —S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂R⁹, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R⁸,    —OCO₂R⁹, —N(R⁸)₂, —OC(═O)N(R⁸)₂, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,    optionally substituted C₁-C₄alkyl, optionally substituted    C₁-C₄fluoroalkyl, optionally substituted C₁-C₄heteroalkyl,    optionally substituted C₃-C₆cycloalkyl, optionally substituted aryl,    or optionally substituted heteroaryl;-   each R⁶ is independently H, optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄heteroalkyl, optionally substituted    C₁-C₄fluoroalkyl, —X-optionally substituted C₁-C₄alkyl,    —X-optionally substituted C₁-C₄heteroalkyl, —X-optionally    substituted C₁-C₄fluoroalkyl, optionally substituted    C₃-C₆cycloalkyl, optionally substituted C₂-C₁₀heterocycloalkyl,    optionally substituted aryl, or optionally substituted heteroaryl;-   or two R⁶ are taken together with the N atom to which they are    attached to form an optionally substituted heterocycle;-   X is —(C═O)—;-   each R⁷ is independently optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄heteroalkyl, optionally substituted    C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl, optionally    substituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl;-   each R⁸ is independently H, optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄heteroalkyl, optionally substituted    C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl, optionally    substituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl;-   or two R⁸ are taken together with the N atom to which they are    attached to form an optionally substituted heterocycle;-   each R⁹ is independently optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄heteroalkyl, or optionally substituted    C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl, optionally    substituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl;-   A² is N or CR^(A);-   R^(A), R^(A1), R^(A2), and R^(A3) are each independently H, halogen,    optionally substituted C₁-C₄alkyl, optionally substituted    C₁-C₄fluoroalkyl, optionally substituted aryl, or —OR¹⁰-   R¹⁰ is independently H, optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄fluoroalkyl, optionally substituted    C₁-C₄heteroalkyl, optionally substituted C₃-C₆cycloalkyl, optionally    substituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl;-   ring A is a monocyclic carbocycle or a monocyclic heterocycle;-   each R³ is independently H, halogen, —CN, —OR¹¹, —SR¹¹, —N(R¹¹)₂,    optionally substituted C₁-C₄alkyl, optionally substituted    C₁-C₄fluoroalkyl, optionally substituted C₁-C₄heteroalkyl,    optionally substituted C₃-C₆cycloalkyl, optionally substituted    C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or optionally    substituted heteroaryl;-   each R¹¹ is independently H, optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄fluoroalkyl, optionally substituted    C₁-C₄heteroalkyl, optionally substituted C₃-C₆cycloalkyl, optionally    substituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl;-   n is 0, 1, 2, 3, or 4;-   R⁴ and R⁵ are each independently H, halogen, —CN, —OR¹², —SR¹²,    —N(R¹²)₂, optionally substituted C₁-C₄alkyl, optionally substituted    C₁-C₄fluoroalkyl, optionally substituted C₁-C₄heteroalkyl,    optionally substituted C₃-C₆cycloalkyl, optionally substituted    C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or optionally    substituted heteroaryl; and-   R¹² is independently H, optionally substituted C₁-C₄alkyl,    optionally substituted C₁-C₄fluoroalkyl, optionally substituted    C₁-C₄heteroalkyl, optionally substituted C₃-C₆cycloalkyl, optionally    substituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl.

In some embodiments,

is substituted C₄-C₇ cycloalkyl that is substituted with 1-3R¹ and0-3R².

In some embodiments,

andq is 0, 1, 2, or 3.

In some embodiments,

q is 0, 1, 2, or 3.

In some embodiments,

and

q is 0, 1, 2, or 3.

In some embodiments, q is 0 or 1. In some embodiments, each R⁶ isindependently H, optionally substituted C₁-C₄alkyl, optionallysubstituted C₁-C₄heteroalkyl, optionally substituted C₁-C₄fluoroalkyl,—X-optionally substituted C₁-C₄alkyl, —X-optionally substitutedC₁-C₄heteroalkyl, or —X-optionally substituted C₁-C₄fluoroalkyl. In someembodiments, each R⁶ is independently H. In some embodiments, each R² isindependently H, optionally substituted C₁-C₄alkyl, optionallysubstituted C₁-C₄heteroalkyl, or optionally substitutedC₁-C₄fluoroalkyl.

In some embodiments

R⁶ is H, optionally substituted C₁-C₄alkyl, optionally substitutedC₁-C₄heteroalkyl, optionally substituted C₁-C₄fluoroalkyl, —X-optionallysubstituted C₁-C₄alkyl, —X-optionally substituted C₁-C₄heteroalkyl, or—X-optionally substituted C₁-C₄fluoroalkyl; q is 0 or 1; and R² is H,optionally substituted C₁-C₄alkyl, optionally substitutedC₁-C₄heteroalkyl, or optionally substituted C₁-C₄fluoroalkyl.

In some embodiments, R⁶ is H. In some embodiments, A² is N. In someembodiments, A² is CR^(A). In some embodiments, R^(A) is H, optionallysubstituted C₁-C₄alkyl, or optionally substituted C₁-C₄fluoroalkyl. Insome embodiments, R^(A) is H. In some embodiments, R^(A1) is H,optionally substituted C₁-C₄alkyl, or optionally substitutedC₁-C₄fluoroalkyl. In some embodiments, R^(A1) is H. In some embodiments,R^(A2) is H, optionally substituted C₁-C₄alkyl, or optionallysubstituted C₁-C₄fluoroalkyl. In some embodiments, R^(A2) is H. In someembodiments, R^(A3) is H, halogen, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄fluoroalkyl, optionally substituted aryl, or—OR¹⁰. In some embodiments, R^(A3) is H, halogen, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄fluoroalkyl, or —OR¹⁰. In someembodiments, R^(A3) is optionally substituted C₁-C₄alkyl. In someembodiments, R^(A3) is methyl, ethyl, propyl or butyl. In someembodiments, R^(A3) is —OR¹⁰ and R¹⁰ is methyl, ethyl, propyl or butyl.In some embodiments, ring A is phenylene or a monocyclicC₃-C₈cycloalkylene that is selected from cyclopropylene, cyclobutylene,cyclopentylene, cyclohexylene, cycloheptylene, and cyclooctylene. Insome embodiments, ring A is phenylene.

In some embodiments,

In some embodiments, ring A is a monocyclic C₁-C₈heteroarylenecontaining 1-4 N atoms, and 0 or 1 O or S atom, or a monocyclicC₁-C₅heteroarylene containing 0-4 N atoms, and 1 O or S atom. In someembodiments, ring A is a monocyclic 6-membered heteroarylene selectedfrom pyridinylene, pyrimidinylene, pyrazinylene, and pyridazinylene. Insome embodiments, ring A is pyridinylene.

In some embodiments,

In some embodiments,

In some embodiments, ring A is a monocyclic 5-membered heteroaryleneselected from furanylene, thienylene, pyrrolylene, oxazolylene,thiazolylene, imidazolylene, pyrazolylene, triazolylene, tetrazolylene,isoxazolylene, isothiazolylene, oxadiazolylene, and thiadiazolylene. Insome embodiments, ring A is oxazolylene, thiazolylene, imidazolylene,pyrazolylene, or oxadiazolylene. In some embodiments, ring A ispyrazolylene.

In some embodiments,

In some embodiments

In some embodiments

In some embodiments, ring A is a ring A is a monocyclicC₂-C₈heterocycloalkylene containing at least 1 N atom in the ring thatis selected from aziridinylene, azetidinylene, pyrrolidinylene,piperidinylene, piperazinylene, and azepanylene. In some embodiments,each R³ is independently H, halogen, —CN, —OR¹¹, —SR¹¹, optionallysubstituted C₁-C₄alkyl, or optionally substituted C₁-C₄fluoroalkyl; andn is 1, 2, or 3. In some embodiments, R³ is optionally substitutedC₁-C₄alkyl.

In some embodiments, R³ is methyl, ethyl, propyl, or butyl. In someembodiments, R³ is —OR¹¹. In some embodiments, R¹¹ is H, optionallysubstituted C₁-C₄alkyl, or optionally substituted C₁-C₄fluoroalkyl. Insome embodiments, R¹¹ is methyl, ethyl, propyl, or butyl. In someembodiments, R¹¹ is —CF₃ or —CH₂CF₃. In some embodiments, R⁴ is H,halogen, —CN, —OR¹², —SR¹², —N(R¹²)₂, optionally substituted C₁-C₄alkyl,or optionally substituted C₁-C₄fluoroalkyl. In some embodiments, R⁴ isH. In some embodiments, R⁴ is halogen. In some embodiments, R⁴ is —Cl,—Br, —F, or —I. In some embodiments, R⁴ is —OR¹². In some embodiments,R¹² is H, optionally substituted C₁-C₄alkyl, or optionally substitutedC₁-C₄fluoroalkyl. In some embodiments, R⁴ is optionally substitutedC₁-C₄alkyl. In some embodiments, R⁴ is methyl, ethyl, propyl, or butyl.In some embodiments, R⁴ is optionally substituted C₁-C₄fluoroalkyl. Insome embodiments, R⁴ is —CF₃ or —CH₂CF₃. In some embodiments, R⁵ is H,halogen, —CN, —OR¹², —SR¹², —N(R¹²)₂, optionally substituted C₁-C₄alkyl,or optionally substituted C₁-C₄fluoroalkyl. In some embodiments, R⁵ isH. In some embodiments, R⁵ is halogen. In some embodiments, R⁵ is —Cl,—Br, —F, or —I. In some embodiments, R⁵ is —OR¹². In some embodiments,R¹² is H, optionally substituted C₁-C₄alkyl, or optionally substitutedC₁-C₄fluoroalkyl. In some embodiments, R⁵ is optionally substitutedC₁-C₄alkyl. In some embodiments, R⁵ is methyl, ethyl, propyl, or butyl.In some embodiments, R⁵ is optionally substituted C₁-C₄fluoroalkyl. Insome embodiments, R⁵ is —CF₃ or —CH₂CF₃.

In some embodiments, the compound has the structure of formula (Ia)

In some embodiments, the compound has the structure of formula (Ib)

In some embodiments, the compound has the structure of formula (Ic)

In some embodiments,

andq is 0 or 1.

In some embodiments, each R⁶ is independently H, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄heteroalkyl, optionallysubstituted C₁-C₄fluoroalkyl, —X-optionally substituted C₁-C₄alkyl,—X-optionally substituted C₁-C₄heteroalkyl, or —X-optionally substitutedC₁-C₄fluoroalkyl. In some embodiments, each R⁶ is independently H. Insome embodiments, each R² is independently H, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄heteroalkyl, or optionallysubstituted C₁-C₄fluoroalkyl. In some embodiments, A² is N. In someembodiments, A² is CR^(A). In some embodiments, R^(A) is H, optionallysubstituted C₁-C₄alkyl, or optionally substituted C₁-C₄fluoroalkyl. Insome embodiments, R^(A) is H. In some embodiments, R^(A1) is H,optionally substituted C₁-C₄alkyl, or optionally substitutedC₁-C₄fluoroalkyl. In some embodiments, R^(A1) is H. In some embodiments,R^(A2) is H, optionally substituted C₁-C₄alkyl, or optionallysubstituted C₁-C₄fluoroalkyl. In some embodiments, R^(A2) is H. In someembodiments, R^(A3) is H, halogen, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄fluoroalkyl, optionally substituted aryl, or—OR¹⁰. In some embodiments, R^(A3) is H, halogen, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄fluoroalkyl, or —OR¹⁰. In someembodiments, R^(A3) is optionally substituted C₁-C₄alkyl. In someembodiments, R^(A3) is methyl, ethyl, propyl, or butyl. In someembodiments, R^(A3) is ethyl. In some embodiments, ring A is phenylene.In some embodiments, ring A is a monocyclic 6-membered heteroaryleneselected from pyridinylene, pyrimidinylene, pyrazinylene, andpyridazinylene. In some embodiments, ring A is pyridinylene. In someembodiments, ring A is a monocyclic 5-membered heteroarylene selectedfrom furanylene, thienylene, pyrrolylene, oxazolylene, thiazolylene,imidazolylene, pyrazolylene, triazolylene, tetrazolylene, isoxazolylene,isothiazolylene, oxadiazolylene, and thiadiazolylene. In someembodiments, ring A is pyrazolylene. In some embodiments, each R³ isindependently H, —OR¹¹, optionally substituted C₁-C₄alkyl, or optionallysubstituted C₁-C₄fluoroalkyl; and n is 1, 2, or 3. In some embodiments,R¹¹ is H, optionally substituted C₁-C₄alkyl, or optionally substitutedC₁-C₄fluoroalkyl. In some embodiments, R⁴ and R⁵ are each independentlyH, halogen, —CN, —OR¹², —SR¹², —N(R¹²)₂, optionally substitutedC₁-C₄alkyl, or optionally substituted C₁-C₄fluoroalkyl.

In some embodiments, the compound has the structure of formula (Id)

and R^(A3) is optionally substituted C₁-C₄ alkyl.

In some embodiments, the compound has the structure of formula (Ie)

In some embodiments, the compound has the structure of formula (If)

In some embodiments, ring A is phenylene, pyridinylene, pyrazolylene,thiazolylene, imidazolylene, oxazolylene, or oxadiazolylene. In someembodiments, R⁴ and R⁵ are each independently H, halogen, —CN, —OR¹²,—SR¹², —N(R¹²)₂, optionally substituted C₁-C₄alkyl, or optionallysubstituted C₁-C₄fluoroalkyl.

In exemplary embodiments, provided herein is a compound of Formula (I),or a pharmaceutically acceptable salt, or solvate thereof:

wherein,

and q is 0, 1, 2, or 3;

each R⁶ is independently H, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄heteroalkyl, optionally substitutedC₁-C₄fluoroalkyl, —X-optionally substituted C₁-C₄alkyl, —X-optionallysubstituted C₁-C₄heteroalkyl, or —X-optionally substitutedC₁-C₄fluoroalkyl;

each R² is independently H, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄heteroalkyl, or optionally substitutedC₁-C₄fluoroalkyl;

A² is N;

R^(A1) is H;

R^(A2) is H, optionally substituted C₁-C₄alkyl, or optionallysubstituted C₁-C₄fluoroalkyl;

R^(A3) is methyl, ethyl, propyl or butyl;

ring A is a monocyclic 6-membered heteroarylene selected frompyridinylene, pyrimidinylene, pyrazinylene, and pyridazinylene;

R³ is independently H, halogen, —CN, —OR¹¹, —SR¹¹, optionallysubstituted C₁-C₄alkyl, or

optionally substituted C₁-C₄fluoroalkyl; and n is 1, 2, or 3; R¹¹ isindependently H, optionally substituted C₁-C₄alkyl, optionallysubstituted C₁-C₄fluoroalkyl, optionally substituted C₁-C₄heteroalkyl,optionally substituted C₃-C₆cycloalkyl, optionally substitutedC₂-C₁₀heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl

R⁴ is —Cl, —Br, —F, or —I;

and R⁵ is hydrogen.

In exemplary embodiments, provided herein is a compound of Formula (I),or a pharmaceutically acceptable salt, or solvate thereof:

wherein,

and q is 0, 1, 2, or 3;

each R⁶ is independently H, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄heteroalkyl, optionally substitutedC₁-C₄fluoroalkyl, —X-optionally substituted C₁-C₄alkyl, —X-optionallysubstituted C₁-C₄heteroalkyl, or —X-optionally substitutedC₁-C₄fluoroalkyl;

each R² is independently H, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄heteroalkyl, or optionally substitutedC₁-C₄fluoroalkyl;

A² is N;

R^(A1) is H;

R^(A2) is H;

R^(A3) is methyl, ethyl, propyl or butyl;

ring A is pyridinylene;

R³ is methyl, ethyl, propyl, or butyl and n is 1, 2 or 3;

R⁴ is —Cl, —Br, —F, or —I;

and R⁵ is hydrogen.

In exemplary embodiments, provided herein is a compound of Formula (I),or a pharmaceutically acceptable salt, or solvate thereof:

wherein.

and q is 0, 1, 2, or 3;

each R⁶ is independently H, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄heteroalkyl, optionally substitutedC₁-C₄fluoroalkyl, —X-optionally substituted C₁-C₄alkyl, —X-optionallysubstituted C₁-C₄heteroalkyl, or —X-optionally substitutedC₁-C₄fluoroalkyl;

each R² is independently H, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄heteroalkyl, or optionally substitutedC₁-C₄fluoroalkyl;

A² is N;

R^(A1) is H;

R^(A2) is H;

R^(A3) is methyl, ethyl, propyl or butyl;

wherein ring A is pyridinylene;

R³ is —OR¹¹ and n is 1, 2 or 3;

R¹¹ is methyl, ethyl, propyl, or butyl

R⁴ is —Cl, —Br, —F, or —I;

and R⁵ is hydrogen.

In exemplary embodiments, provided herein is a compound of Formula (I),or a pharmaceutically acceptable salt, or solvate thereof:

wherein,

and q is 0, 1, 2, or 3;

each R⁶ is independently H, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄heteroalkyl, optionally substitutedC₁-C₄fluoroalkyl, —X-optionally substituted C₁-C₄alkyl, —X-optionallysubstituted C₁-C₄heteroalkyl, or —X-optionally substitutedC₁-C₄fluoroalkyl;

each R² is independently H, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄heteroalkyl, or optionally substitutedC₁-C₄fluoroalkyl;

A² is N;

R^(A1) is H;

R^(A2) is H;

R^(A3) is methyl, ethyl, propyl or butyl;

wherein ring A is pyridinylene;

R³ is —OR¹¹ and n is 1, 2 or 3;

R¹¹ is CF₃ or —CH₂CF₃

R⁴ is —Cl, —Br, —F, or —I;

and R⁵ is hydrogen.

In some embodiments, a compound described herein is selected from anyone of the compounds from Table 1.

TABLE 1 Compound No. Structure Name 1

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2- chlorobenzenesulfonamide 2

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-3-methylphenyl)-2- chlorobenzenesulfonamide 3

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-methylphenyl)-2- chlorobenzenesulfonamide 4

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-4-methylpyridin-2-yl)-2- chlorobenzenesulfonamide 5

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-4-methylpyridin-2-yl)-2- chlorobenzenesulfonamide 6

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2- chlorobenzenesulfonamide 7

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-methylphenyl)-2- (trifluoromethyl) benzenesulfonamide 8

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-methylphenyl)-2- (trifluoromethoxy) benzenesulfonamide 9

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-methylphenyl)-2,5- dichlorobenzenesulfonamide 10

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-methylphenyl)-2- fluorobenzenesulfonamide 11

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-3-methylphenyl)-3- chlorobenzenesulfonamide 12

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino-8- ethylquinazolin-6-yl)-3-methylphenyl)-4- chlorobenzenesulfonamide 13

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino-8- ethylquinazolin-6-yl)-3-methylphenyl)-2- methoxybenzenesulfonamide 14

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-(trifluoromethyl)phenyl)-2- chlorobenzenesulfonamide 15

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-methylphenyl) benzenesulfonamide 16

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-2- chlorobenzenesulfonamide 17

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-chlorophenyl)-2- chlorobenzenesulfonamide 18

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)phenyl)- 2-chlorobenzenesulfonamide 19

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-methoxyphenyl)-2- chlorobenzenesulfonamide 20

N-(6-2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-5-methylpyridin-3-yl)-2- chlorobenzenesulfonamide 21

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-2-fluoro-5-methylphenyl)-2- chlorobenzenesulfonamide 22

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2,3- dimethylphenyl)-2- chlorobenzenesulfonamide23

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-4-methylpyrimidin-2-yl)-2- chlorobenzenesulfonamide 24

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino-8- ethylquinazolin-6-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 25

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyrazin- 2-yl)-2- chlorobenzenesulfonamide 26

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)phenyl-2-chlorobenzenesulfonamide 27

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridin- 2-yl)-2- chlorobenzenesulfonamide 28

N-(6-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridin- 3-yl)-2- chlorobenzenesulfonamide 29

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-1H-pyrazol-3-yl)-2- chlorobenzenesulfonamide 30

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-hydroxyquinazolin-6-yl)-3- methylphenyl)-2-chloro-N-methylbenzenesulfonamide 31

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-methylphenyl)-2-chloro-N- methylbenzenesulfonamide 32

N-(6-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)pyridazin-3-yl)-2- chlorobenzenesulfonamide 33

N-(2-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)pyrimidin-5-yl)-2- chlorobenzenesulfonamide 34

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-ethylphenyl)-2- chlorobenzenesulfonamide 35

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-fluorophenyl)-2- chlorobenzenesulfonamide 36

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-methoxyquinazolin-6-yl)-3- methylphenyl)-2- chlorobenzenesulfonamide 37

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2- chlorobenzenesulfonamide 38

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-4-methylthiazol-2-yl)-2- chlorobenzenesulfonamide 39

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)pyrimidin-2-yl)-2- chlorobenzenesulfonamide 40

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-isopropylquinazolin-6-yl)-1- methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide 41

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)thiazol-2- yl)-2- chlorobenzenesulfonamide 42

N-(4-(2-(((1r,4r))-4- aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluoro- 5-methoxyphenyl)-2-chlorobenzenesulfonamide 43

N-(1-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-1H-pyrazol-4-yl)-2- chlorobenzenesulfonamide 44

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)isoxazol- 3-yl)-2- chlorobenzenesulfonamide 45

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-methoxyquinazolin-6-yl)-1- methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide 46

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-4-methoxypyrimidin-2-yl)-2- chlorobenzenesulfonamide 47

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- propylquinaozlin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2- chlorobenzenesulfonamide 48

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-3-fluorophenyl)-2- chlorobenzenesulfonamide 49

N-(6-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)pyridazin-3-yl)-2- chlorobenzenesulfonamide 50

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 51

N-(6-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-5-fluoropyridin-3-yl)-2- chlorobenzenesulfonamide 52

N-(6-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-5-fluoropyridin-3-yl)-2- chlorobenzenesulfonamide 53

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-2,5-difluorophenyl)-2- chlorobenzenesulfonamide 54

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-3-fluoropyridin-2-yl)-2- chlorobenzenesulfonamide 55

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-fluoropyridin-2-yl)-2- chlorobenzenesulfonamide 56

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-2,3-difluorophenyl)-2- chlorobenzenesulfonamide 57

N-(4-(3-(((1r,4r)-4- aminocyclohexyl)amino) isoquinolin-7-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 58

(S)-2-amino-N-((1r,4S)-4-((6- (4-((2- chlorophenyl)sulfonamido)-3-fluorophenyl)-8- ethylquinazolin-2- yl)amino)cyclohexyl)-3-methylbutanamide 59

N-((1r,4r)-4-((6-(4-((2- chlorophenyl)sulfonamido)-3- fluorophenyl)-8-ethylquinazolin-2- yl)amino)cyclohexyl) acetamide 60

2-chloro-N-(4-(8-ethyl-2- (((1r,4r)-4- (methylamino)cyclohexyl)amino)quinazolin-6-yl)-2- fluorophenyl) benzenesulfonamide 62

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-3,5-difluorophenyl)-2- chlorobenzenesulfonamide 63

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino-8- ethylquinazolin-6-yl)-2,6-difluorophenyl)-2- chlorobenzenesulfonamide 65

N-(6-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinaolin-6-yl)-5-methoxypyridazin-3-yl)-2- chlorobenzenesulfonamide 66

N-(6-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-4-methxoypyridazin-3-yl)-2- chlorobenzenesulfonamide 67

N-(6-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-5-methylpyridazin-3-yl)-2- chlorobenzenesulfonamide 68

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-4-methylpyrimidin-2-yl)-2- chlorobenzenesulfonamide 69

2-chloro-N-(4-(2-(((1r,4r)-4- (dimethylamino)cyclohexyl)amino)-8-ethylquinazolin- 6-yl)-2- fluorophenyl) benzenesulfonamide 70

N-(4-(2-(((1R,3R,4S)-4- amino-3- methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-2- fluorophenyl)-2- chlorobenzenesulfonamide 71

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluoro- 3-methylphenyl)-2-chlorobenzenesulfonamide 72

N-(4-(2-(((1R,3S)-3- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 73

(S)-2-chloro-N-(4-(8-ethyl-2- (piperidin-3- ylamino)quinazolin-6-yl)-2-fluorophenyl) benzenesulfonamide 74

N-(4-(2-(((1R,3R,4R)-4- amino-3- methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-2- fluorophenyl)-2- chlorobenzenesulfonamide 75

N-(4-(2-(((1R,3S)-3- aminocyclohexyl)amino) quinazolin-6-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 76

(S)-2-chloro-N-(2-fluoro-4-(2- (piperidin-3- ylamino)quinazolin-6-yl)phenyl)benzenesulfonamide 77

N-(4-(2-(((1R,3R)-3- aminocyclopentyl)amino) quinazolin-6-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 78

N-(4-(2-(((1R,3R)-3- aminocyclopentyl)amino)-8- ethylquinazolin-6-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 79

N-(4-(2-(((1R,3S)-3- aminocyclopentyl)amino)-8- ethylquinazolin-6-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 80

N-(4-(2-(((1R,3S)-3- aminocyclopentyl)amino) quinazolin-6-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 81

N-(4-(2-((4- aminobicyclo[2.2.2]octan-1- yl)amino)quinazolin-6-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 82

N-(4-(2-(((2r,5r)-5- aminooctahydropentalen-2-yl)amino)-8-ethylquinazolin- 6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide 83

N-(4-(2-(((2r,5r)-5- aminooctahydropentalen-2-yl)amino)-8-ethylquinazolin- 6-yl-2-fluorophenyl)-2-chlorobenzenesulfonamide 84

N-(4-(2-(((2s,5s)-5- aminooctahydropentalen-2-yl)amino)-8-ethylquinazolin- 6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide 85

N-(4-(2-(((2s,5s)-5- aminooctahydropentalen-2-yl)amino)quinazolin-6-yl)-2- fluorophenyl)-2- chlorobenzenesulfonamide86

N-(4-(2-((4- aminobicyclo[2.2.1]heptan-1- yl)amino)quinazolin-6-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 87

N-(4-(2-((4- aminobicyclo[2.2.2]octan-1- yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 88

2-chloro-N-(4-(8-ethyl-2- (((1r,4r)-4-(pyrrolidin-1-yl)cyclohexyl)amino) quinazolin-6-yl)-2- fluorophenyl)benzenesulfonamide 89

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino) quinazolin-6-yl)-1,3,4-thiadiazol-2-yl)-2- chlorobenzenesulfonamide 90

N-(4-(2-(((1r,4r)-4- aminocyclohexyl)amino)-7- methylquinazolin-6-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide 92

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-4-methoxypyridin-2-yl)-2- chlorobenzenesulfonamide 93

N-(6-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-5-methoxypyridin-3-yl)-2- chlorobenzenesulfonamide 94

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-6-methylpyrazin-2-yl)-2- chlorobenzenesulfonamide 96

N-(6-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-5-ethylpyridazin-3-yl)-2- chlorobenzenesulfonamide 98

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-6-methxoypyrazin-2-yl)-2- chlorobenzenesulfonamide 100

N-(6-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-4-ethylpyridazin-3-yl)-2- chlorobenzenesulfonamide 101

2-chloro-N-(5-(8-ethyl-2- (((1r,4r)-4- hydroxycyclohexyl)amino)quinazolin-6-yl)-6- metthoxypyridin-2- yl)benzenesulfonamide 102

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-7- methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2- cyanobenzenesulfonamide 103

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2- methylbenzenesulfonamide 104

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-7- methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2- chlorobenzenesulfonamide 105

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-7- methylquinazolin-6-yl)-6-ethylpyridin-2-yl)-2- chlorobenzenesulfonamide 106

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-7- methylquinazolin-6-yl)-6-methylpyridin-2-yl)-2- chlorobenzenesulfonamide 107

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-6-(trifluoromethoxy)pyridin-2- yl)-2- chlorobenzenesulfonamide 109

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2- methoxybenzenesulfonamide 110

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-7- ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2- chlorobenzenesulfonamide 111

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-6-methylpyridin-2- yl)benzenesulfonamide 112

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-2- methylbenzenesulfonamide 113

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-3- methylbenzenesulfonamide 114

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-5- methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2- chlorobenzenesulfonamide 115

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8- methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2- chlorobenzenesulfonamide 120

2-chloro-N-(4-(2-(((1r,4r)-4- (dimethylamino)cyclohexyl)amino)-8-ethylquinazolin- 6-yl)-2-fluoro-5- methoxyphenyl)benzenesulfonamide 121

2-chloro-N-(4-(8-ethyl-2- (((1r,4r)-4- (methylamino)cyclohexyl)amino)quinazolin-6-yl)-2- fluoro-5- methoxyphenyl) benzenesulfonamide123

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-(1,1-difluoroethyl)quinazlin- 6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide 129

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-(methoxymethyl)quinazolin-6- yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide 134

N-(5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-8-(trifluoromethyl)quinazolin-6- yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide 136

2-chloro-N-(5-(2-((4- (dimethylamino)bicyclo[2.2.2] octan-1-yl)amino)-8-ethylquinazolin-6-yl)-6- ethylpyridin-2- yl)benzenesulfonamide 138

N-(5-(2-(((1s,4s)-4- aminocyclohexyl)amino)-8- methylquinazlin-6-yl)-6-methoxypyridin-2-yl)-2- chlorobenzenesulfonamide 140

N-(5-(2-(((1s,4s)-4- aminocyclohexyl)amino)-8- ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2- chlorobenzenesulfonamide 143

2-chloro-N-(5-(2-(((1s,4s)-4- (dimethylamino)-4-methylcyclohexyl)amino)-8- ethylquinazolin-6-yl)-6- methoxypyridin-2-yl)benzenesulfonamide 144

2-chloro-N-(5-(2-(((1s,4s)-4- (dimethylamino)-4-methylcyclohexyl)amino)-8- ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2- yl)benzenesulfonamide 146

N-(5-(2-(((1s,4s)-4- aminocyclohexyl)amino)-8- methylquinazlin-6-yl)-3-fluoro-6-methoxypyridin-2- yl)-2- chlorobenzenesulfonamideIRE1-like Family of Proteins

In some embodiments, a compound disclosed herein selectively binds to aprotein of the serine/threonine-protein kinase/endoribonucleaseinositol-requiring enzyme 1 (IRE1) family of proteins. In humans, IRE1is encoded by the ERN1 gene. Exemplary IRE1 family proteins includeisoforms IRE1 and IRE1a. Other exemplary IRE1 family proteins includeIRE1 homologues or orthologues in other organisms. Exemplary organismsinclude human, non-human primate, mouse, rat, chicken, fruit fly, yeast,and others listed in Table 2. In some embodiments, the IRE1 protein ishuman IRE1a.

TABLE 2 Organism Accession # Homo sapiens NP_001424.3 Mus musculusNP_076402.1 Rattus norvegicus XP_006247696.1

In some embodiments, a compound disclosed herein selectively binds to anIRE1 family protein comprising a kinase domain and/or an RNase domain.In some embodiments, the kinase domain is a trans-autophosphorylationkinase domain. In some embodiments, the IRE1 family protein is IRE1a. Anexample arrangement of domains within an IRE1a protein is depicted inFIG. 1. An example alignment of IRE1 family protein orthologues isdepicted in FIG. 2.

In some embodiments, a compound disclosed herein selectively binds to atrans-autophosphorylation kinase domain region of IRE1a. In someembodiments, a compound disclosed herein selectively binds to atrans-autophosphorylation kinase domain region of IRE1a, for examplewithin amino acid residues 568-833 of SEQ ID NO: 1, or equivalent aminoacid residues thereof.

In some embodiments, a compound disclosed herein selectively binds to anATP-binding pocket within a trans-autophosphorylation kinase domainregion of IRE1a. In some embodiments, a compound disclosed hereinselectively binds to an ATP-binding pocket within atrans-autophosphorylation kinase domain region of IRE1a, for example,one or more of amino acid resides 577-711, 577-586, 597, 599, 626,642-643, 645, 648, 688, 692-693, 695, or 711 of SEQ ID NO: 1, orequivalent amino acid residues thereof.

In some embodiments, a compound disclosed herein selectively binds to anactivation loop within a trans-autophosphorylation kinase domain regionof IRE1a. In some embodiments, a compound disclosed herein selectivelybinds to an activation loop within a trans-autophosphorylation kinasedomain region of IRE1a, for example, one or more of amino acid residues710-736, 710-725, or 729-736 of SEQ ID NO: 1, or equivalent amino acidresidues thereof.

In some embodiments, a compound disclosed herein selectively binds to anRNase domain region of IRE1a. In some embodiments, a compound disclosedherein selectively binds to an RNase domain region of IRE1a, for examplewithin amino acid residues 835-963 of SEQ ID NO: 1, or equivalent aminoacid residues thereof.

In some embodiments, a compound disclosed herein selectively binds to akinase domain dimer interface amino acid residue. In some embodiments, acompound disclosed herein selectively binds to a kinase domain dimerinterface amino acid residue, such as one or more of amino acid residues569-701, 569, 591, 592, 594, 617, 620,627, 628, 631, 674, 678, or 701 ofSEQ ID NO: 1.

In some embodiments, a compound disclosed herein selectively binds to afirst IRE1a and blocks dimerization between kinase domain dimerinterface amino acid residues of the first IRE1a and a second IRE1a. Insome embodiments, a compound disclosed herein selectively binds to afirst IRE1a, and inhibit dimerization at one or more of amino acidresidues 569-701, 569, 591, 592, 594, 617, 620,627, 628, 631, 674, 678,or 701 of SEQ ID NO: 1.

In some embodiments, a compound disclosed herein selectively binds to akinase-extension nuclease (KEN) domain dimer interface amino acidresidue of an IRE1a. In some embodiments, a compound disclosed hereinselectively binds to a KEN domain dimer interface amino acid residue,such as one or more of amino acid residues 840-925, 840, 844, 851, 908,912, or 925 of SEQ ID NO: 1.

In some embodiments, a compound disclosed herein selectively binds toamino acid residues of a nuclease active site. In some embodiments, acompound disclosed herein selectively binds to amino acid residues of anuclease active site, such as one or more of amino acid residues847-910, 847, 850, 886, 888, 889, 890, 892, 902, 905, 906, or 910 of SEQID NO: 1.

In some embodiments, a compound disclosed herein selectively binds to anRNase domain and a trans-autophosphorylation kinase domain region ofIRE1a. In some embodiments, a compound disclosed herein selectivelybinds to an RNase domain and an ATP-binding pocket within atrans-autophosphorylation kinase domain region of IRE1a. In someembodiments, a compound disclosed herein selectively binds to an RNasedomain and an activation loop within a trans autophosphorylation kinasedomain region of IRE1a.

In some embodiments, a compound disclosed herein selectively binds toIRE1a at two sites located in an RNase domain, trans-autophosphorylationkinase domain region, ATP-binding pocket, activation loop, or anycombination thereof. In some embodiments, a compound disclosed hereinselectively binds to IRE1a at two or more sites. In some embodiments, acompound disclosed herein selectively binds to IRE1a at two or moresites located in an RNase domain, trans-autophosphorylation kinasedomain region, ATP-binding pocket, activation loop, or any combinationthereof. In some embodiments, a compound disclosed herein selectivelybinds to IRE1a at three sites located in an RNase domain,trans-autophosphorylation kinase domain region, ATP-binding pocket,activation loop, or any combination thereof.

In some embodiments, a compound disclosed herein selectively binds toIRE1a at a first site located in an RNase domain,trans-autophosphorylation kinase domain region, ATP-binding pocket, oractivation loop. In some embodiments, a first site comprises one or moreof any amino acid residue within amino acid residues 465-977 of SEQ IDNO: 1. In some embodiments, a compound disclosed herein selectivelybinds to IRE1a at a second site located in an RNase domain,trans-autophosphorylation kinase domain region, ATP-binding pocket, oractivation loop. In some examples, the first site is located within thesame domain or region as the second site. In some examples, the firstsite is located within a different domain or region as the second site.

In some embodiments, a compound disclosed herein selectively binds tofirst IRE1a, thereby blocking dimerization of the first IRE1a to asecond IRE1a. In some embodiments, a compound disclosed hereinselectively binds to first IRE1a, thereby blockingauto-transphosphorylation of the first IRE1a or a second IRE1a to whichthe first IRE1a is dimerized. In some embodiments, a compound disclosedherein selectively binds to a first IRE1a, thereby blocking activationof the first IRE1a or a second IRE1a to which the first IRE1a isdimerized. In some embodiments, a compound disclosed herein selectivelybinds to a first IRE1a, thereby blocking kinase activity of the firstIRE1a or a second IRE1a to which the first IRE1a is dimerized. In someembodiments, a compound disclosed herein selectively binds to a firstIRE1a, thereby blocking RNase activity of the first IRE1a or a secondIRE1a to which the first IRE1a is dimerized.

In some embodiments, a compound disclosed herein selectively binds toIRE1a when in a homo-dimerized conformation. In some embodiments, acompound disclosed herein selectively binds to IRE1a when in anoligomerized conformation. In some embodiments, a compound disclosedherein selectively binds to IRE1a when in a non-oligomerized ornon-dimerized conformation. In some embodiments, a compound disclosedherein selectively binds to IRE1a when in an ATP-bound state. In someembodiments, a compound disclosed herein selectively binds to a IRE1family protein when in a non-ATP-bound state. In some embodiments, thecompound is a pharmaceutically acceptable salt, or solvate thereof.

IRE1 Signaling Pathway

In some embodiments, a compound disclosed herein selectively binds to anIRE1 family protein and alters a downstream signaling pathway. In someembodiments, a compound disclosed herein selectively binds to an IRE1family protein and alters signaling of immunoglobulin heavy-chainbinding protein (BIP), protein kinase R (PKR)-like endoplasmic reticulumkinase (PERK), glucose regulate protein 78 (Grp78), eukaryotictranslation initiation factor 2α (eIF2α), X-box binding protein 1(XBP1), activating transcription factor 6a (ATF6α), C/EBP homologousprotein (CHOP), growth arrest and DNA damage-inducible protein 34(GADD34), tumor necrosis factor receptor-associated factor 2 (TRAF2),JUN N-terminal kinase (JNK), regulated IRE1-dependent decay (RIDD),transcriptionally active XBP1 (XBP1s), or unspliced XBP1 (XBP1u). Insome embodiments, a compound disclosed herein selectively binds to anIRE1 family protein and alters a downstream cellular process. In someembodiments, an IRE1 family protein is IRE1, IRE1a, or ERN1.

In some embodiments, a compound disclosed herein selectively binds to anIRE1 family protein and decreases or blocks a downstream signalingpathway. In some embodiments, a compound disclosed herein selectivelybinds to an IRE1 family protein and decreases or blocks activity orsignaling of TXNIP, Caspase 1, Interleukin 1-beta, JNK, Bim, cytochromeC, Caspase 3, Caspase 8, mRNA degradation, miRNA degradation,apoptotosis-inducing proteins, or inflammation-inducing proteins. Insome embodiments, a compound disclosed herein selectively binds to anIRE1 family protein and decreases XBP1 mRNA levels. In some embodiments,a compound disclosed herein selectively binds to an IRE1 family proteinand decreases transcriptionally active XBP1 (XBP1s) mRNA levels. In someembodiments, a compound disclosed herein selectively binds to an IRE1family protein and decreases spliced XBP1 mRNA levels. In someembodiments, an IRE1 family protein is IRE1, IRE1a, or ERN1.

In some embodiments, a compound disclosed herein selectively binds to anIRE1 family protein and increases, activates, or removes a block of adownstream signaling pathway. In some embodiments, a compound disclosedherein selectively binds to an IRE1 family protein and increases,activates, or removes a block of activity or signaling of Bcl2, Bcl-XL,Mcl-1, Bax, Bak, other anti-apoptotic proteins, or an mRNA transloconproteins. In some embodiments, an IRE1 family protein is IRE1, IRE1a, orERN1.

In some embodiments, a compound disclosed herein selectively binds to anIRE family protein and disrupts binding with an effector protein. Insome cases, the effector protein binds to the IRE1 family protein whenin a dimerized or oligomerized state. In some cases, the effectorprotein binds to the IRE1 family protein when in a non-dimerized ornon-oligomerized state. In some cases, the effector protein isimmunoglobulin heavy-chain binding protein (BIP), protein kinase R(PKR)-like endoplasmic reticulum kinase (PERK), glucose regulate protein78 (Grp78), tumor necrosis factor receptor-associated factor 2 (TRAF2),JUN N-terminal kinase (JNK), transcriptionally active XBP1 (XBP1s),unspliced XBP1 (XBP1u), regulated IRE1-dependent decay (RIDD), Heatshock protein 90 kDa alpha (HSP 90-alpha), or misfolded protein. In someembodiments, an IRE1 family protein is IRE1, IRE1a, or ERN1.

In some embodiments, a compound disclosed herein selectively binds to anIRE1 family protein and alters activity of a cellular process orcellular function, such as regulated

IRE1-dependent decay (RIDD), RNA decay, translation, autophagy, cellsurvival, ER protein folding, ERAD, reactive oxygen species generation,transport, ER-associated protein degradation (ERAD), protein synthesis,or apoptosis. In some embodiments, where an altered or lack of acellular process or cellular function is associate with a disease state,selective binding of a compound disclosed herein results in inhibitingor alleviating the disease state, or inhibiting a deleterious activityassociated with the disease state. In some embodiments, an IRE1 familyprotein is IRE1, IRE1a, or ERN1.

Diseases Associated with Altered IRE1 Pathway Signaling

In some cases, a compound disclosed herein is used to treat orameliorate a disease associated with altered IRE1a pathway signalingwhen administered to a subject in need thereof. In some cases, acompound disclosed herein is used to treat or ameliorate the effects ofa disease associated with altered IRE1a pathway signaling whenadministered to a subject in need thereof. Exemplary disease associatedwith altered IRE1a signaling include cancer. In some cases, a compounddisclosed herein is used to treat or ameliorate a cancer whenadministered to a subject in need thereof. Exemplary cancers includetumors, solid and hematologic cancers. In some cases, a compounddisclosed herein is used to treat or ameliorate a cell proliferativedisorder when administered to a subject in need thereof. In some cases,the cell proliferative disorder is a cancer. In some cases, the canceris ovarian cancer, lung cancer, bladder cancer, breast cancer, or triplenegative breast cancer (TNBC).

An IRE1a pathway can be involved in a variety of pathologicalconditions, including neurodegenerative diseases, inflammation,metabolic disorders, liver dysfunction, brain ischemia, heart ischemia,autoimmune diseases, and cancer. In some cases, modulation of thispathway provides therapeutic methods useful for treatment of suchdiseases.

In some instances, a compound disclosed herein is used to reinforceanti-tumor mechanisms. In some cases, an anti-tumor mechanism comprisesdirect inhibition of tumor growth. In some cases, an anti-tumormechanism comprises induction of anti-tumor immunity. In some cases,anti-tumor mechanisms comprise direct inhibition of tumor growth andsimultaneous induction of anti-tumor immunity. In some cases, a compounddisclosed herein can prevent lipid accumulation in myeloid cells exposedto ovarian cancer-derived ascites supernatants. In some cases, acompound disclosed herein can block myeloid cell immunosuppressionmediated by tumor-associated factors. In some cases, a compounddisclosed herein can be employed as therapeutic compound that enhancesdendritic cell and T cell anti-tumor activity in mammals. For example,the compounds disclosed herein can be used to treat murine and humanovarian cancers.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds described herein, or a pharmaceuticallyacceptable salt thereof, are used in the preparation of medicaments forthe treatment of diseases or conditions in a mammal that would benefitfrom administration of any one of the compounds disclosed. Methods fortreating any of the diseases or conditions described herein in a mammalin need of such treatment, involves administration of pharmaceuticalcompositions that include at least one compound described herein or apharmaceutically acceptable salt, active metabolite, prodrug, orpharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said mammal.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in patients, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, who previously experienced at least one symptom of thedisease being treated and is currently in remission, a pharmaceuticalcomposition comprising a compound described herein, or apharmaceutically acceptable salt thereof, in order to prevent a returnof the symptoms of the disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered is temporarily reduced or temporarilysuspended for a certain length of time (e.g., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, ormore than 28 days. The dose reduction during a drug holiday is, by wayof example only, by 10%-100%, including by way of example only 10%, 15%,20%, 25%), 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg to 5000 mg per day. In one aspect,doses employed for adult human treatment are from about 1 mg to about1000 mg per day. In one embodiment, the desired dose is convenientlypresented in a single dose or in divided doses administeredsimultaneously or at appropriate intervals, for example as two, three,four or more sub-doses per day.

In one embodiment, the daily dosages appropriate for the compounddescribed herein, or a pharmaceutically acceptable salt thereof, arefrom about 0.01 mg/kg to about 50 mg/kg per body weight. In someembodiments, the daily dosage or the amount of active in the dosage formare lower or higher than the ranges indicated herein, based on a numberof variables in regard to an individual treatment regime. In variousembodiments, the daily and unit dosages are altered depending on anumber of variables including, but not limited to, the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD50 and the ED50. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD50 and ED50. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe ED50 with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound described herein, or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by injection to the mammal; and/or (e) administeredtopically to the mammal; and/or (f) administered non-systemically orlocally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce a day; or (ii) the compound is administered to the mammal multipletimes over the span of one day, e.g., two, three, four or more timesdaily.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

In certain instances, it is appropriate to administer at least onecompound described herein, or a pharmaceutically acceptable saltthereof, in combination with one or more other therapeutic agents. Inone embodiment, the therapeutic effectiveness of one of the compoundsdescribed herein is enhanced by administration of an adjuvant {i.e., byitself the adjuvant has minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, in some embodiments, the benefit experiencedby a patient is increased by administering one of the compoundsdescribed herein with another agent (which also includes a therapeuticregimen) that also has therapeutic benefit.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors (e.g. the disease, disorder orcondition from which the subject suffers; the age, weight, sex, diet,and medical condition of the subject). Thus, in some instances, thedosage regimen actually employed varies and, in some embodiments,deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

The compounds described herein, or a pharmaceutically acceptable saltthereof, as well as combination therapies, are administered before,during or after the occurrence of a disease or condition, and the timingof administering the composition containing a compound varies. Thus, inone embodiment, the compounds described herein are used as aprophylactic and are administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. In another embodiment, thecompounds and compositions are administered to a subject during or assoon as possible after the onset of the symptoms. In specificembodiments, a compound described herein is administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease. In some embodiments, the length required for treatment varies,and the treatment length is adjusted to suit the specific needs of eachsubject. For example, in specific embodiments, a compound describedherein or a formulation containing the compound is administered for atleast 2 weeks, about 1 month to about 5 years.

Examples I. Chemical Synthesis

In some embodiments, the compounds that modulate IRE1 mediated signalingdisclosed herein are synthesized according to the following examples.The examples are intended to illustrate but not limit the disclosedembodiments.

Example 1A: Synthesis of tert-butyl((1r,4r)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(1A)

Step 1: 6-bromoquinazolin-2-amine (1A-2)

To a solution of 5-bromo-2-fluoro-benzaldehyde (20.0 g, 98.5 mmol) inDMA (700 mL) was added guanidine-carbonic acid (26.6 g, 147.7 mmol). Themixture was stirred at 160° C. for 0.5 h, cooled to rt and concentrated.The residue was diluted with H₂O (300 mL) and extracted with ethylacetate (200 mL×3). The combined organic layers were washed with brine(100 mL×3), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was washed with DCM (300 mL) toget compound 1A-2 (4.0 g, crude).

Step 2: 6-bromo-2-iodoquinazoline (1A-3)

To a solution of compound 1A-2 (2.0 g, 8.9 mmol) in THF (20.0 mL) underN₂ were added of isoamylnitrite (3.1 g, 26.8 mmol, 3.6 mL),diiodomethane (11.9 g, 44.7 mmol, 3.6 mL) and CuI (1.7 g, 8.9 mmol). Themixture was stirred at 80° C. for 2 h, cooled to rt, quenched byaddition of ice water (100 mL), and extracted with ethyl acetate (100mL×3). The combined organic layers were washed with brine (100 mL×3),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography (SiO₂) to afford compound 1A-3 (2.1 g,crude).

Step 3: 1-tert-butyl ((1r,4r)-4-((6-bromoquinazolin-2-yl)amino)cyclohexyl)carbamate (1A-4)

To a solution of compound 1A-3 (4.0 g, 11.9 mmol) in IPA (120.0 mL) wasadded DIEA (4.6 g, 35.8 mmol, 6.2 mL) and tert-butyl((1r,4r)-4-aminocyclohexyl)carbamate (7.6 g, 35.8 mmol). The mixture wasstirred at 80° C. for 12 h, cooled to rt and filtered. The collectedsolid was washed with Dichloromethane/Methanol (10/1, 60 mL). Thecombined filtrate was concentrated to give a residue which was purifiedby column chromatography (SiO₂) to afford compound 1A-4 (3.6 g, 6.8mmol, 57.2% yield). M+H⁺=421.1 (LCMS); ¹H NMR (CHLOROFORM-d, 400 MHz) δ8.87 (s, 1H), 7.78 (d, J=1.8 Hz, 1H), 7.71 (dd, J=2.0, 9.0 Hz, 1H), 7.44(d, J=9.2 Hz, 1H), 5.19 (br d, J=7.9 Hz, 1H), 4.43 (br s, 1H), 3.93 (brd, J=7.5 Hz, 1H), 3.49 (br s, 1H), 2.27-2.00 (m, 4H), 1.46 (s, 9H),1.40-1.29 (m, 4H)

Step 4: tert-butyl((1r,4r)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(1A)

A mixture of compound 1A-4 (2.0 g, 4.7 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.3 g, 5.2 mmol), AcOK (1.4 g, 14.2 mmol) and Pd(dppf)Cl₂ (347 mg,474.6 umol) in dioxane (50 mL) was degassed and purged with N₂ threetimes, and heated at 90° C. for 12 h under N₂. The reaction was cooledto rt and concentrated to give a residue. The residue was purified bycolumn chromatography (SiO₂) to afford compound 1A (2.7 g, crude).M+H⁺=469.2 (LCMS).

Example 2A: Synthesis of tert-butyl((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(2A)

Step 1: 1-(5-bromo-2-fluorophenyl)ethan-1-ol (2A-2)

A solution of 5-bromo-2-fluoro-benzaldehyde (55.0 g, 270.9 mmol) in THF(500.0 mL) was cooled to 0° C. Then MeMgBr (3 M, 94.8 mL) was added. Themixture was stirred at 0° C. for 0.5 h, quenched with NH₄Cl (500 mL) andextracted with ethyl acetate (500 mL×3). The combined organic layerswere washed with brine (500 mL×3), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂) to afford compound 2A-2 (46.0g, crude).

Step 2: 4-bromo-2-ethyl-1-fluorobenzene (2A-3)

To a solution of compound 2A-2 (46.0 g, 210.0 mmol) and triethylsilane(48.8 g, 420.0 mmol, 66.9 mL) in DCM (500.0 mL) was added BF₃.Et₂O (59.6g, 420.0 mmol, 51.8 mL) at 0° C. The mixture was stirred at 25° C. for 2h, concentrated, quenched by addition of Sat.NaHCO₃ (200 mL) at 0° C.,and extracted with ethyl acetate (200 mL×3). The combined organic layerswere washed with brine (200 mL×3), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂)to afford compound 2A-3 (24.0 g, crude). H NMR (CHLOROFORM-d, 400 MHz) δ7.31 (dd, J=2.2, 6.6 Hz, 1H), 7.27-7.21 (m, 1H), 6.87 (t, J=9.2 Hz, 1H),2.62 (q, J=7.5 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H).

Step 3: 5-bromo-3-ethyl-2-fluorobenzaldehyde (2A-4)

To a solution of compound 2A-3 (24.0 g, 82.7 mmol) in THF (500 mL) wasadded LDA (2 M, 49.6 mL) at −78° C. The mixture was stirred at −78° C.for 1 h. Then dimethyl formamide (7.8 g, 107.5 mmol, 8.3 mL) was addedand stirred for 1 h at −78° C. The reaction mixture was quenched byaddition of NH₄Cl (100 mL) and the resulting mixture was extracted withethyl acetate (200 mL×3). The combined organic layers were washed withbrine (100 mL×3), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂) to afford compound 2A-4 (13.0 g, crude). ¹H NMR(CDCl₃, 400 MHz) δ 10.30 (s, 1H), 7.81 (dd, J=2.6, 5.7 Hz, 1H), 7.58(dd, J=2.6, 6.4 Hz, 1H), 2.73 (q, J=7.6 Hz, 2H), 1.30-1.25 (m, 3H)

Step 4: 6-bromo-8-ethylquinazolin-2-amine (2A-5)

To a solution of carbonic acid-guanidine (3.5 g, 19.4 mmol) and DIEA(5.0 g, 38.9 mmol, 6.8 mL) in DMA (20 mL) was added a solution ofcompound 2A-4 (3.0 g, 12.98 mmol) in DMA (5 mL). The mixture was stirredat 160° C. for 1 h, poured into ice water (30 mL) and extracted withethyl acetate (40 mL×3). The combined organic layers were washed withbrine (30 mL×3), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂) to afford compound 2A-5 (1.2 g, crude). ¹H NMR(DMSO-d₆, 400 MHz) δ 9.03 (s, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.60 (d,J=2.4 Hz, 1H), 6.94 (s, 2H), 2.98-2.88 (m, 2H), 1.22-1.17 (m, 3H)

Step 5: 6-bromo-8-ethyl-2-iodoquinazoline (2A-6)

To a mixture of compound 2A-5 (1.2 g, 4.76 mmol) and CH₂I₂(6.3 g, 23.8mmol, 1.92 mL) in tetrahydrofuran (24.0 mL) were added CuI (906 mg, 4.7mmol) and isoamyl nitrite (1.6 g, 14.3 mmol, 2.0 mL). After the mixturewas stirred at 80° C. for 2 h under N₂, NH₃.H₂O (30 mL) was added. Theresulting mixture was extracted with ethyl acetate (50 mL×3) and thecombined organic layers were washed with brine (50 mL×3), dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography (SiO₂) to afford compound 2A-6 (400 mg, crude).

Step 6: tert-butyl((1r,4r)-4-((6-bromo-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(2A-7)

To a mixture of compound 2A-6 (350 mg, 964.2 umol) and DIEA (373 mg, 2.8mmol, 505.2 uL) in isopropanol (10 mL) was added tert-butyl((1r,4r)-4-aminocyclohexyl)carbamate (413 mg, 1.9 mmol). The mixture wasstirred at 80° C. for 12 h, cooled to rt and concentrated. The residuewas purified by prep-TLC (SiO₂) to afford compound 2A-7 (350 mg, crude).

Step 7: tert-butyl((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(2A)

To a mixture of compound 2A-7 (150 mg, 333.7 umol) and KOAc (98 mg, 1.0mmol) in dioxane (2 mL) were added4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(101 mg, 400.5 umol) and Pd(dppf)Cl₂ (24 mg, 33.3 umol). The mixture wasstirred at 90° C. for 12 h under N₂, cooled to rt and concentrated. Theresidue was purified by prep-TLC (SiO₂) to afford compound 2A (100 mg,crude).

Example 1: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide(1)

Step 1

To a solution of tert-butyl((1r,4r)-4-((6-bromoquinazolin-2-yl)amino)cyclohexyl)carbamate (700 mg,1.6 mmol) in Boc₂O (46.0 mL) was added TEA (505 mg, 5.0 mmol, 690.9 uL)and DMAP (406 mg, 3.3 mmol). The mixture was stirred at 100° C. for 12h, cooled to rt and diluted with DCM (50 mL). Silica gel was added andthe resulting suspension was concentrated to give residue which waspurified by column chromatography (SiO2) to afford tert-butyl((1r,4r)-4-(bis(tert-butoxycarbonyl)amino)cyclohexyl)(6-bromoquinazolin-2-yl)carbamate(340 mg, 437.6 umol, 43.9% yield). 1H NMR (CHLOROFORM-d, 400 MHz): δ9.25 (s, 1H), 8.06 (d, J=1.8 Hz, 1H), 7.96-7.91 (m, 1H), 7.86-7.81 (m,1H), 4.25 (br t, J=11.6 Hz, 1H), 3.89 (br t, J=11.8 Hz, 1H), 2.08-1.93(m, 4H), 1.87-1.73 (m, 4H), 1.46 (s, 18H), 1.41 (s, 9H).

Step 2

A mixture of tert-butyl((1r,4r)-4-(bis(tert-butoxycarbonyl)amino)cyclohexyl)(6-bromoquinazolin-2-yl)carbamate(340 mg, 547.0 umol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(153 mg, 601.7 umol), AcOK (161 mg, 1.6 mmol) and Pd(dppf)Cl₂ (40 mg,54.7 umol) in dioxane (5.0 mL) was degassed and purged with N₂ threetimes, and then the mixture was stirred at 90° C. for 12 h under N₂. Thereaction was cooled to rt and concentrated to give a residue which waspurified by column chromatography (SiO₂) to afford(2-(((1r,4r)-4-(bis(tert-butoxycarbonyl)amino)cyclohexyl)(tert-butoxycarbonyl)amino)quinazolin-6-yl)boronicacid (400 mg, 504.7 umol, 92.2% yield).

Step 3

A mixture of(2-(((1r,4r)-4-(bis(tert-butoxycarbonyl)amino)cyclohexyl)(tert-butoxycarbonyl)amino)quinazolin-6-yl)boronicacid (330 mg, 562.6 umol), 5-bromo-1-methyl-1H-pyrazol-3-amine (119 mg,675.2 umol), K₂CO₃ (233 mg, 1.6 mmol) and Pd(dppf)Cl₂ (41 mg, 56.2 umol)in dioxane (15.0 mL) and H₂O (1.5 mL) was degassed and purged with N₂three times, and the mixture was stirred at 90° C. for 12 h under N₂.The reaction was concentrated and the residue was purified by columnchromatography (SiO₂) to afford tert-butyl(6-(3-amino-1-methyl-1H-pyrazol-5-yl)quinazolin-2-yl)((1r,4r)-4-(bis(tert-butoxycarbonyl)amino)cyclohexyl)carbamate(120 mg, crude).

Step 4

To a solution of tert-butyl(6-(3-amino-1-methyl-1H-pyrazol-5-yl)quinazolin-2-yl)((1r,4r)-4-(bis(tert-butoxycarbonyl)amino)cyclohexyl)carbamate(60 mg, 94.0 umol) in pyridine (2.0 mL) was added TEA (29 mg, 282.2umol, 39.1 uL) and 2-chlorobenzenesulfonyl chloride (50 mg, 235.2 umol,32.0 uL). The mixture was stirred at 25° C. for 12 h and concentrated.The residue was purified by prep-TLC (SiO₂) to afford tert-butyl((1r,4r)-4-(bis(tert-butoxycarbonyl)amino)cyclohexyl)(6-(3-((2-chlorophenyl)sulfonamido)-1-methyl-1H-pyrazol-5-yl)quinazolin-2-yl)carbamate(80 mg, crude).

Step 5

To a solution of tert-butyl((1r,4r)-4-(bis(tert-butoxycarbonyl)amino)cyclohexyl)(6-(3-((2-chlorophenyl) sulfonamido)-1-methyl-1H-pyrazol-5-yl)quinazolin-2-yl)carbamate(80 mg, 98.4 umol) in DCM (2.0 mL) was added TFA (1.0 mL). The mixturewas stirred at 25° C. for 15 min and concentrated to give a residue. Theresidue was dissolved in MeOH (2.0 mL), basified with NH₃.H₂O (0.02 mL,25% solution) and concentrated to give a residue. The residue waspurified by prep-HPLC to affordN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide(36.1 mg, 61.5 umol, 62.4% yield, FA). M+H⁺=512.3 (LCMS). ¹H NMR(METHANOL-d₄, 400 MHz): δ 9.05 (s, 1H), 8.33 (br s, 1H), 8.07 (dd,J=1.1, 7.9 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 7.68 (dd, J=2.0, 8.8 Hz,1H), 7.60-7.50 (m, 3H), 7.42 (ddd, J=1.9, 6.6, 8.1 Hz, 1H), 6.11 (s,1H), 4.01-3.88 (m, 1H), 3.70 (s, 3H), 3.13 (tdd, J=4.0, 7.8, 11.6 Hz,1H), 2.26-2.05 (m, 4H), 1.66-1.39 (m, 4H).

The following compound was synthesized according to procedures describedin example 1 above for the preparation of compound 1.

Comp Mass ¹H NMR (MeOD, 400 ID Structure Chemical Name (M + H⁺) MHz) 6

N-(5-(2- (((1r,4r)-4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-1-methyl- 1H-pyrazol-3-yl)- 2- chlorobenzene- sulfonamide, Calc'dfor C₂₆H₃₁ClN₇O₂S: 540.2; Found: 540.2 δ 9.01 (s, 1H), 8.48 (br s, 1H),8.09 (dd, J = 1.1, 7.9 Hz, 1H), 7.63-7.49 (m, 4H), 7.43 (dt, J = 1.9,7.3 Hz, 1H), 6.10 (s, 1H), 4.04-3.91 (m, 1H), 3.71 (s, 3H), 3.16 (tt, J= 3.6, 11.4 Hz, 1H), 3.05 (q, J = 7.5 Hz, 2H), 2.30 (br d, J = 11.2formate Hz, 2H), 2.14 (br d, J = salt 11.7 Hz, 2H), 1.69- 1.41 (m, 4H),1.31 (t, J = 7.5 Hz. 3H)

Example 2: Synthesis ofN-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3-methylphenyl)-2-chlorobenzenesulfonamide(2)

Step 1

To a solution of 2-chlorobenzenesulfonyl chloride (170 mg, 806.2 umol,109.7 uL) in DCM (2.0 mL) was added pyridine (63 mg, 806.2 umol, 65.0uL) and 4-bromo-3-methyl-aniline (100 mg, 537.4 umol). The mixture wasstirred at 45° C. for 2 h. The reaction mixture was concentrated underreduced pressure. The residue was purified by prep-TLC (SiO2) to affordN-(4-bromo-3-methylphenyl)-2-chlorobenzenesulfonamide (190 mg, 447.8umol, 83.3% yield).

Step 2

A mixture of N-(4-bromo-3-methylphenyl)-2-chlorobenzenesulfonamide (50mg, 138.6 umol), tert-butyl((1r,4r)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(64 mg, 138.6 umol), K₂CO₃ (57 mg, 415.9 umol), Pd(dppf)Cl₂ (10 mg, 13.8umol) in dioxane (2.0 mL) and H₂O (0.2 mL) was degassed and purged withN₂ three times, and then the mixture was stirred at 90° C. for 12 hunder N₂ atmosphere. The reaction mixture was concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂) to affordtert-butyl((1r,4r)-4-((6-(4-(2-chlorophenylsulfonamido)-2-methylphenyl)quinazolin-2-yl)amino)cyclohexyl)carbamate(30 mg, crude). M+H⁺=622.2 (LCMS).

Step 3

To a solution of tert-butyl((1r,4r)-4-((6-(4-(2-chlorophenylsulfonamido)-2-methylphenyl)quinazolin-2-yl)amino)cyclohexyl)carbamate(30 mg, 48.2 umol) in DCM (2.0 mL) was added TFA (1.0 mL). The mixturewas stirred at 25° C. for 0.5 h. The reaction mixture was concentratedunder reduced pressure. The residue was added dichloromethane (2.0 mL)and NH₃.H₂O (25% solution) to pH 7, concentrated under reduced pressureagain. The residue was purified by prep-HPLC to giveN-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3-methylphenyl)-2-chlorobenzenesulfonamide(6.9 mg, 12.1 umol, 25.2% yield, FA). M+H⁺=522.0 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 9.04 (s, 1H), 8.57 (s, 1H), 8.23-8.04 (m, 1H),7.66-7.53 (m, 5H), 7.50-7.43 (m, 1H), 7.14-7.04 (m, 3H), 4.10-3.87 (m,1H), 3.16 (tt, J=3.9, 11.6 Hz, 1H), 2.25 (br d, J=10.5 Hz, 2H), 2.20 (s,3H), 2.14 (br d, J=12.1 Hz, 2H), 1.70-1.39 (m, 4H).

The following compound was synthesized according to procedures describedin example 2 above for the preparation of compound 2.

Comp Mass ¹H NMR (MeOD, 400 ID Structure Chemical Name (M + H⁺) MHz) 5

N-(5-(2- (((1r,4r)-4- aminocyclohexyl) amino) quinazolin-6-yl)-4-methylpyridin- 2-yl)-2- chlorobenzene- Calc'd for C₂₆H₂₈ClN₆O₂S:523.2; Found: 523.2 δ 9.05 (s, 1H), 8.52 (br s, 1H), 8.22 (d, J = 7.5Hz, 1H), 7.82 (s, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.67-7.62 (m, 1H),7.61-7.55 (m, 1H), 7.55-7.52 (m, 1H), 7.50-7.45 (m, 1H), sulfonamide,7.38-7.30 (m, 1H), formate 7.15 (s, 1H), 4.06-3.90 salt (m, 1H),3.24-3.05 (m, 1H), 2.31-2.20 (m, 5H), 2.12 (br d, J = 12.3 Hz, 2H),1.69-1.40 (m, 4H)

Example 3: Synthesis ofN-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)-2-chlorobenzenesulfonamide(3)

Step 1

A mixture of N-(4-bromo-3-methylphenyl)-2-chlorobenzenesulfonamide (29mg, 80.5 umol), tert-butyl((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(40 mg, 80.5 umol), K₂CO₃ (16 mg, 120.8 umol), Pd(dppf)Cl₂ (5 mg, 8.0umol) in dioxane (2.0 mL) and water (0.2 mL) was degassed and purgedwith N₂ three times. The mixture was stirred at 90° C. for 12 h underN₂, cooled to rt, and concentrated. The residue was purified by prep-TLC(SiO2) to give tert-butyl((1r,4r)-4-((6-(4-(2-chlorophenylsulfonamido)-2-methylphenyl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(47 mg, 58.6 umol, 72.7% yield). M+H⁺=650.3 (LCMS).

Step 2

To a solution of tert-butyl((1r,4r)-4-((6-(4-(2-chlorophenylsulfonamido)-2-methylphenyl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(47 mg, 72.2 umol) in DCM (2.0 mL) was added TFA (1.0 mL). The resultingmixture was stirred at 15° C. for 0.5 h and concentrated. The residuewas dissolved in MeOH (2.0 mL), basified pH to 8 with NH₃.H₂O (25%solution) and purified by prep-HPLC to giveN-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)-2-chlorobenzenesulfonamide(10.2 mg, 17.2 umol, 23.8% yield, FA). M+H⁺=550.2 (LCMS); ¹H NMR (400MHz, METHANOL-d₄): δ 8.95 (d, J=4.2 Hz, 1H), 8.39 (br s, 1H), 8.09 (d,J=7.7 Hz, 1H), 7.60-7.51 (m, 2H), 7.47-7.37 (m, 3H), 7.11-7.01 (m, 3H),4.01-3.91 (m, 1H), 3.17 (tt, J=3.7, 11.4 Hz, 1H), 3.04 (q, J=7.5 Hz,2H), 2.31 (brd, J=11.9 Hz, 2H), 2.19-2.10 (m, 5H), 1.66-1.54 (m, 2H),1.54-1.43 (m, 2H), 1.34-1.27 (m, 3H).

The following compounds were synthesized according to proceduresdescribed in example 3 above for the preparation of compound 3.

Comp Mass ¹H NMR (MeOD, 400 ID Structure Chemical Name (M + H⁺) MHz)  4

N-(5-(2- (((1r,4r)-4- aminocyclohexyl) amino)-8- ethylquinazlin-6-yl)-4- methylpyridin-2- yl)-2- chlorobenzene- sulfonamide, Calc'd forC₂₈H₃₂ClN₆O₂S: 551.2 Found: 551.2 δ 9.00 (s, 1 H), 8.49 (br s, 1 H),8.22 (d, J = 7.34 Hz, 1 H), 7.80 (s, 1 H), 7.45-7.58 (m, 5 H), 7.14 (s,1 H), 3.91-4.03 (m, 1 H), 3.10-3.21 (m, 1 H), 3.06 (q, J = 7.66 Hz, 2H), 2.31 (br d, J = 13.20 Hz, 2 H), 2.25 (s, 3 H), 2.13 (br d, J =formate 12.23 Hz, 2 H), 1.44- salt 1.64 (m, 4 H), 1.31 (t, J = 7.58 Hz,3 H) 14

N-(4-(2- (((1r,4r)-4- aminocyclohexyl) amino)-8- ethylquinazlin-6-yl)-3- (trifluoromethyl) phenyl)-2- chlorobenzene- sulfonamide, Calc'dfor C₂₉H₃₀ClF₃N₅O₂S: 604.2; Found: 604.2 δ 8.95 (br s, 1H), 8.55 (br s,1H), 8.15 (d, J = 7.7 Hz, 1H), 7.63-7.53 (m, 3H), 7.48 (br dd, J = 4.3,7.2 Hz, 1H), 7.41 (br d, J = 7.9 Hz, 3H), 7.26 (br d, J = 8.4 Hz, 1H),4.02-3.92 (m, 1H), 3.21-3.11 (m, 1H), 3.03 (q, J = 7.3 Hz, formate 2H),2.31 (br d, J = 11.7 salt Hz, 2H), 2.14 (br d, J = 11.5 Hz, 2H), 1.65-1.55 (m, 2H), 1.54- 1.43 (m, 2H), 1.29 (t, J = 7.5 Hz, 3H). 16

N-(5-(2- (((1r,4r)-4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-6- methylpyridin-2- yl)-2- chlorobenzene- sulfonamide, Calc'd forC₂₈H₃₂ClN₆O₂S: 551.2; Found: 551.1 δ 9.02 (s, 1H), 8.56 (br s, 1H),8.33-8.19 (m, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.61-7.44 (m, 5H), 7.22 (brd, J = 8.8 Hz, 1H), 4.08-3.89 (m, 1H), 3.25-3.15 (m, 1H), 3.09 (q, J =7.5 Hz, 2H), 2.40 (s, 3H), 2.33 (br d, J = 11.5 Hz, 2H), formate salt2.17 (br d, J = 11.5 Hz, 2H), 1.70-1.46 (m, 4H), 1.34 (t, J = 7.5 Hz,3H). 17

N-(4-(2- (((1r,4r)-4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-3- chlorophenyl)-2- chlorobenzene- sulfonamide, formate saltCalc'd for C₂₈H₃₀Cl₂N₅O₂S: 570.1; Found: 570.1 δ 8.97 (s, 1H), 8.56 (brs, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.63-7.56 (m, 2H), 7.56-7.52 (m, 2H),7.48 (ddd, J = 3.3, 5.3, 8.2 Hz, 1H), 7.33- 7.23 (m, 2H), 7.17 (dd, J =2.2, 8.4 Hz, 1H), 4.05- 3.90 (m, 1H), 3.20- 3.10 (m, 1H), 3.04 (q, J =7.4 Hz, 2H), 2.31 (br d, J = 11.7 Hz, 2H), 2.13 (br d, 7= 11.9 Hz, 2H),1.65-1.54 (m, 2H), 1.54-1.43 (m, 2H), 1.31 (t, J = 7.5 Hz, 3H) 19

N-(4-(2- (((1r,4r)-4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-3- methoxyphenyl)- 2- chlorobenzene- sulfonamide, Calc'd forC₂₉H₃₃ClN₅O₃S: 566.2; Found: 566.2 δ 8.94 (s, 1 H), 8.51 (br s, 1 H),8.10-8.18 (m, 1 H), 7.63 (d, J = 1.76 Hz, 1 H), 7.54-7.60 (m, 3 H), 7.46(ddd, J = 8.16, 5.84, 2.76 Hz, 1 H), 7.18 (d, J = 8.16 Hz, 1 H), 6.90(d, J = 1.98 Hz, 1 H), 6.81 (dd, J = 8.16, 1.98 Hz, 1 H), 3.91- formate4.04 (m, 1 H), 3.73 (s, 3 salt H), 3.12-3.23 (m, 1 H), 3.03 (q, J = 7.57Hz, 2 H), 2.31 (br d, J = 11.03 Hz, 2H), 2.14 (br d, J = 12.13 Hz, 2 H),1.43- 1.67 (m, 4 H), 1.30 (t, J = 7.39 Hz, 3 H) 20

N-(6-(2- (((1r,4r)-4- aminocyclohexyl) amino)-8- ethylquinazlin-6-yl)-5- methylpyridin-3- yl)-2- chlorobenzene- sulfonamide, Calc'd forC₂₈H₃₂ClN₆O₂S: 551.2; Found: 551.2 δ 9.00 (s, 1 H), 8.53 (br s, 1 H),8.23 (s, 1 H), 8.14 (d, J = 7.94 Hz, 1 H), 7.57-7.64 (m, 4 H), 7.55 (s,1 H), 7.45-7.51 (m, 1 H), 3.90-4.05 (m, 1 H), 3.16 (br t, J = 11.36 Hz,1 H), 3.07 (q, J = 7.64 Hz, 2 H), 2.26- 2.36 (m, 5 H), 2.14 (br formated, J = 10.80 Hz, 2 H), salt 1.44-1.68 (m, 4 H), 1.32 (t, J = 7.50 Hz, 3H) 21

N-(4-(2- (((1r,4r)-4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl-2-f-luoro-5- methylphenyl)-2- chlorobenzene- sulfonamide, formatesalt Calc'd for C₂₉H₃₃ClFN₅O₃S: 568.2; Found: 568.2 δ 8.96 (s, 1H), 8.51(br s, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.66-7.50 (m, 2H), 7.49-7.37 (m,3H), 7.30 (d, J = 7.9 Hz, 1H), 6.99-6.88 (m, 1H), 4.03-3.90 (m, 1H),3.17 (br t, J = 11.5 Hz, 1H), 3.04 (q, J = 7.4 Hz, 2H), 2.31 (br d, J =11.5 Hz, 2H), 2.15 (

, 5H), 1.67-1.55 (m, 2H), 1.54-1.43 (m, 2H), 1.30 (t, J = 7.4 Hz, 3H) 22

N-(4-(2- (((1r,4r)-4- aminocyclohexyl) amino)-8- ethylquinazlin-6-yl)-2,3- dimethylphenyl)- 2- chlorobenzene- sulfonamide, Calc'd forC₃₀H₃₅ClN₅O₂S: 564.2; Found: 564.2 δ 8.97 (s, 1 H), 8.55 (br s, 1 H),7.88 (dd, J = 8.31, 1.47 Hz, 1 H), 7.64-7.68 (m, 1 H), 7.56-7.61 (m, 1H), 7.38-7.44 (m, 3 H), 6.90-6.93 (m, 1 H), 6.82-6.88 (m, 1 H),3.93-4.02 (m, 1 H), 3.12-3.21 (m, 1 H), formate 3.06 (q, J = 7.34 Hz, 2salt H), 2.32 (br d, J = 11.74 Hz, 2 H), 2.26 (s, 3 H), 2.14 (m, 5 H),1.44- 1.67 (m, 4 H), 1.31 (t, J = 7.34 Hz, 3 H)

Example 4: Synthesis ofN-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)phenyl)-2-chlorobenzenesulfonamide(18)

Step 1

A mixture of 4-bromoaniline (33 mg, 193.3 umol), tert-butyl((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(80 mg, 161.1 umol), K₂CO₃ (33 mg, 241.7 umol), Pd(dppf)Cl₂ (11 mg, 16.1umol) in dioxane (2.0 mL) and water (0.2 mL) was degassed and purgedwith N₂. The resulting mixture was stirred at 90° C. for 12 h under N₂.Additional 4-bromoaniline (13 mg) and Pd(dppf)Cl₂ (10 mg) were added,and the mixture was stirred at 90° C. for 4 h, cooled to rt andconcentrated. The residue was purified by prep-TLC (SiO₂) to givetert-butyl((1r,4r)-4-((6-(4-aminophenyl)-8-ethylquinazolin-2-yl)amino)-cyclohexyl)carbamate(40 mg, 65.2 umol, 40% yield). M+H⁺=462.3 (LCMS).

Step 2

To a solution of tert-butyl((1r,4r)-4-((6-(4-aminophenyl)-8-ethylquinazolin-2-yl)amino)-cyclohexyl)carbamate(40 mg, 86.6 umol) in DCM (2.0 mL) was added pyridine (20 mg, 259.9umol, 20.9 uL) and 2-chlorobenzenesulfonyl chloride (18 mg, 86.6 umol,11.8 uL). The mixture was stirred at 45° C. for 12 h, cooled to rt andconcentrated to give tert-butyl((1r,4r)-4-((6-(4-(2-chlorophenylsulfonamido)phenyl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(50 mg, crude).

Step 3

To a solution of tert-butyl((1r,4r)-4-((6-(4-(2-chlorophenylsulfonamido)phenyl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(50 mg, 78.5 umol) in DCM (2.0 mL) was added TFA (1.0 mL). The mixturewas stirred at 15° C. for 0.5 h and concentrated. The residue wasdissolved in MeOH (2.0 mL), basified pH to 8 with NH₃.H₂O (25% solution)and purified by prep-HPLC to giveN-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)phenyl)-2-chlorobenzenesulfonamide(8.7 mg, 14.9 umol, 18.9% yield, FA). M+H⁺=536.2 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 9.00 (s, 1H), 8.50 (br s, 1H), 8.12-8.03 (m, 1H),7.74 (dd, J=1.9, 16.2 Hz, 2H), 7.60-7.48 (m, 4H), 7.47-7.38 (m, 1H),7.24 (d, J=8.6 Hz, 2H), 4.02-3.92 (m, 1H), 3.17 (tt, J=3.9, 11.5 Hz,1H), 3.07 (q, J=7.4 Hz, 2H), 2.31 (br d, J=11.9 Hz, 2H), 2.14 (br d,J=11.7 Hz, 2H), 1.67-1.55 (m, 2H), 1.54-1.42 (m, 2H), 1.33 (t, J=7.5 Hz,3H). The following compounds were synthesized according to proceduresdescribed in example 4 above for the preparation of compound 18.

Comp Mass ¹H NMR (MeOD, ID Structure Chemical Name (M + H⁺) 400 MHz) 7

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-3- methylphenyl)-2- (trifluoromethyl) benzene- sulfonamide, formatesalt Calc'd for C₃₀H₃₃F₃N₅O₂S: 584.2; Found: 584.2 δ 8.96 (s, 1H), 8.53(br s, 1H), 8.18- 8.11 (m, 1H), 7.97- 7.90 (m, 1H), 7.80- 7.68 (m, 2H),7.43 (d, J = 6.2 Hz, 2H), 7.15-7.08 (m, 1H), 7.07-6.97 (m, 2H),4.05-3.90 (m, 1H), 3.16 (tt, J = 3.8, 11.5 Hz, 1H), 3.05 (q, J = 7.5 Hz,2H), 2.31 (br d, J = 11.7 Hz, 2H), 2.21-2.08 (m, 5H), 1.68-1.40 (m, 4H),1.30 (t, J = 7.5 Hz, 3H) 8

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-3- methylphenyl)-2- (trifluoro- methoxy) benzene- sulfonamide,formate salt Calc'd for C₃₀H₃₃F₃N₅O₃S: 600.2; Found: 600.2 δ 8.95 (s,1H), 8.57 (br s, 1H), 8.02 (dd, J = 1.7, 7.8 Hz, 1H), 7.73-7.62 (m, 1H),7.52-7.34 (m, 4H), 7.12-6.95 (m, 3H), 4.03-3.88 (m, 1H), 3.20-3.09 (m,1H), 3.04 (q, J = 7.5 Hz, 2H), 2.30 (br d, J = 11.7 Hz, 2H), 2.19- 2.06(m, 5H), 1.65- 1.40 (m, 4H), 1.30 (t, J = 7.4 Hz, 3H) 9

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-3- methylphenyl)- 2,5- dichlorobenzene- sulfonamide, formate saltCalc'd for C₂₉H₃₂Cl₂N₅O₃S: 584.2; Found: 584.1 δ 8.95 (s, 1H), 8.56 (brs, 1H), 8.07- 8.00 (m, 1H), 7.59- 7.53 (m, 2H), 7.47- 7.39 (m, 2H),7.14- 7.00 (m, 3H), 4.02- 3.89 (m, 1H), 3.18- 3.08 (m, 1H), 3.04 (q, J =7.5 Hz, 2H), 2.35-2.25 (m, 2H), 2.19 (s, 3H), 2.12 (br d, J = 11.9 Hz,2H), 1.64-1.40 (m, 4H), 1.30 (t, J = 7.5 Hz, 3H) 10

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-3- methylphenyl)-2- fluorobenzene- sulfonamide, formate salt Calc'dfor C₂₉H₃₃FN₅O₃S: 534.2; Found: 534.1 δ 8.96 (s, 1 H), 8.57 (br s, 1 H),7.88 (td, J = 7.55, 1.65 Hz, 1 H), 7.46-7.72 (m, 2 H), 7.43 (dd, J =8.71, 1.87 Hz, 2 H), 7.25-7.33 (m, 2 H), 7.03-7.10 (m, 2 H), 3.91-4.05(m, 1 H), 3.10-3.20 (m, 1 H), 2.98-3.09 (m, 2 H), 2.28-2.34 (m, 2 H),2.07-2.22 (m, 5 H), 1.42-1.65 (m, 4 H), 1.28-1.37 (m, 3 H) 11

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8-ethyl- quinazolin-6-yl)-3- methylphenyl)-3- chlorobenzene- sulfonamide, formate salt Calc'd forC₂₉H₃₃ClN₅O₃S: 550.2; Found: 550.2 δ 8.98 (s, 1H), 8.56 (br s, 1H),7.81- 7.77 (m, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.60 (br d, J = 7.9 Hz,1H), 7.52 (d, J = 7.9 Hz, 1H), 7.49-7.45 (m, 2H), 7.17-7.12 (m, 1H),7.07-6.99 (m, 2H), 4.04-3.91 (m, 1H), 3.18-3.10 (m, 1H), 3.06 (q, J =7.5 Hz, 2H), 2.32 (br d, J = 10.5 Hz, 2H), 2.21 (s, 3H), 2.13 (br d, J =12.3 Hz, 2H), 1.64-1.42 (m, 4H), 1.32 (t, J = 7.5 Hz, 3H) 12

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8-ethyl- quinazolin-6-yl)-3- methylphenyl)-4- chlorobenzene- sulfonamide, formate salt Calc'd forC₂₉H₃₃ClN₅O₃S: 550.2; Found: 550.2 δ 8.98 (s, 1 H), 8.54 (br s, 1 H),7.74- 7.82 (m, 2 H), 7.53 (d, J = 8.82 Hz, 2 H), 7.44-7.48 (m, 2 H),7.13 (d, J = 7.72 Hz, 1 H), 6.98-7.05 (m, 2 H), 3.92-4.04 (m, 1 H),3.11-3.25 (m, 1 H), 3.01-3.09 (m, 2 H), 2.32 (br d, J = 10.36 Hz, 2 H),2.20 (s, 3 H), 2.15 (br d, J = 11.69 Hz, 2 H), 1.43-1.66 (m, 4 H), 1.32(t, J = 7.39 Hz, 3 H) 13

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-3- methylphenyl)-2- methoxybenzene- sulfonamide, formate salt Calc'dfor C₃₀H₃₆N₅O₃S: 546.2; Found: 546.2 δ 9.01 (br s, 1H), 7.84 (dd, J =1.5, 7.7 Hz, 1H), 7.64- 7.49 (m, 2H), 7.42 (d, J = 7.0 Hz, 2H), 7.15 (d,J = 8.3 Hz, 1H), 7.12-6.95 (m, 4H), 3.99 (m, 4H), 3.20-3.00 (m, 3H),2.31 (m, 2H), 2.17 (m, 5H), 1.63-1.39 (m, 4H), 1.30 (t, J = 7.5 Hz, 3H)15

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-3- methylphenyl) benzene- sulfonamide, formate salt Calc'd forC₂₉H₃₄N₅O₃S: 516.2; Found: 516.2 δ 8.95-8.75 (m, 1H), 8.35 (br s, 1H),7.76-7.70 (m, 2H), 7.51-7.44 (m, 1H), 7.43-7.37 (m, 2H), 7.32 (dd, J =1.8, 14.6 Hz, 2H), 7.02-6.97 (m, 1H), 6.95-6.90 (m, 2H), 3.89 (tdd, J =3.8, 7.5, 11.1 Hz, 1H), 3.09 (br t, J = 11.5 Hz, 1H), 2.95 (q, J = 7.5Hz, 2H), 2.22 (br d, J = 11.1 Hz, 2H), 2.14-2.01 (m, 5H), 1.63-1.30 (m,4H), 1.21 (t, J = 7.5 Hz, 3H)

Exemplary compounds were synthesized according to procedures describedherein. For compounds that do not have a specific synthetic schemedescribed herein, such compounds can be routinely synthesized by askilled artisan armed with the guidance presented herein and skill inthe art.

Comp Mass ¹H NMR (MeOD, 400 ID Structure Chemical Name (M + H⁺) MHz) 23

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-4- methylpyrimidin- 2-yl)-2- chlorobenzene- sulfonamide Calc'd forC₂₇H₃₁ClN₇O₂S: 552.1; Found: 552.1 δ 9.01 (s, 1H), 8.58 (br s, 1H), 8.34(br d, J = 7.0 Hz, 1H), 8.23 (br s, 1H), 7.61-7.46 (m, 5H), 4.05-3.89(m, 1H), 3.26-3.13 (m, 1H), 3.07 (q, J = 7.5 Hz, 2H), 2.31 (m, 5H), 2.16(br d, J = 10.6 Hz, 2H), 1.71-1.43 (m, 4H), 1.33 (t, J = 7.5 Hz, 3H) 24

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-2- fluorophenyl)-2- chlorobenzene- sulfonamide Calc'd forC₂₈H₃₀ClFN₅O₂S: 554.2; Found: 554.1 δ 9.03 (s, 1H), 8.56 (br s, 1H),8.03 (dd, J = 1.3, 7.9 Hz, 1H), 7.80 (s, 2H), 7.68-7.54 (m, 2H),7.54-7.34 (m, 4H), 4.05-3.91 (m, 1H), 3.25-3.15 (m, 1H), 3.09 (q, J =7.4 Hz, 2H), 2.33 (br d, J = 11.5 Hz, 2H), 2.16 (br d, J = 11.7 Hz, 2H),1.71- 1.43 (m, 4H), 1.41- 1.27 (m, 3H) 25

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)pyrazin-2- yl)-2- chlorobenzene- sulfonamide Calc'd forC₂₆H₂₉ClN₇O₂S: 538.2; Found: 538.1 δ 9.03 (s, 1H), 8.58 (br s, 2H),8.33-8.23 (m, 2H), 8.13 (d, J = 1.7 Hz, 1H), 8.08 (d, J = 1.8 Hz, 1H),7.57-7.44 (m, 3H), 4.06-3.91 (m, 1H), 3.26-3.14 (m, 1H), 3.08 (q, J =7.4 Hz, 2H), 2.32 (br d, J = 10.5 Hz, 2H), 2.16 (br d, J = 13.0 Hz, 2H),1.73- 1.44 (m, 4H), 1.38- 1.27 (m, 3H) 26

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)quinazolin- 6-yl)phenyl)-2-chlorobenzene- sulfonamide M + H⁺ = 508.1 (LCMS) ¹H NMR (400 MHz,METHANOL-d₄) δ 9.06 (s, 1H), 8.41 (br s, 1H), 8.14-8.06 (m, 1H),7.99-7.88 (m, 2H), 7.62-7.49 (m, 5H), 7.43 (m, 1H), 7.25 (d, J = 8.7 Hz,2H), 4.02- 3.89 (m, 1H), 3.21- 3.10 (m, 1H), 2.23 (br d, J = 12.0 Hz,2H), 2.12 (br d, J = 11.0 Hz, 2H), 1.67-1.55 (m, 2H), 1.53-1.41 (m, 2H)27

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)pyridin-2- yl)-2- chlorobenzene- sulfonamide Calc'd forC₂₇H₃₀ClN₆O₂S: 537.2; Found: 537.1 δ 9.03 (s, 1 H), 8.55 (br s, 1 H),8.40 (d, J = 2.45 Hz, 1 H), 8.05-8.15 (m, 3 H), 7.80 (d, J = 8.80 Hz, 1H), 7.68 (dd, J = 8.56, 2.69 Hz, 1 H), 7.53- 7.61 (m, 2 H), 7.41- 7.50(m, 1 H), 3.92- 4.03 (m, 1 H), 3.12- 3.21 (m, 1 H), 3.08 (q, J = 7.34Hz, 2 H), 2.31 (br d, J = 11.25 Hz, 2 H), 2.14 (br d, J = 11.74 Hz, 2H), 1.42-1.64 (m, 4 H), 1.34 (t, J = 7.58 Hz, 3H) 28

N-(6-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)pyridin-3- yl)-2- chlorobenzene- sulfonamide Calc'd forC₂₇H₃₀ClN₆O₂S: 537.2; Found: 537.2 δ 9.00 (s, 1H), 8.53 (br s, 1H), 8.30(s, 1H), 8.23 (d, J = 7.7 Hz, 1H), 8.06 (dd, J = 2.0, 8.8 Hz, 1H), 7.76(s, 2H), 7.55- 7.44 (m, 3H), 7.29 (d, J = 9.0 Hz, 1H), 4.01- 3.90 (m,1H), 3.21-3.11 (m, 1H), 3.07 (q, J = 7.4 Hz, 2H), 2.30 (br d, J = 10.8Hz, 2H), 2.13 (br d, J = 12.1 Hz, 2H), 1.66- 1.40 (m, 4H), 1.33 (t, J =7.5 Hz, 3H) 29

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-1H-pyrazol- 3-yl)-2- chlorobenzene- sulfonamide Calc'd forC₂₅H₂₉ClN₇O₂S: 526.2; Found: 526.1 δ 8.99 (s, 1H), 8.09 (d, J = 7.3 Hz,1H), 7.78 (br s, 2H), 7.62-7.52 (m, 2H), 7.43 (t, J = 7.2 Hz, 1H), 6.37(s, 1H), 3.96 (m, 1H), 3.17 (m, 1H), 3.05 (q, J = 7.3 Hz, 2H), 2.30 (brd, J = 11.5 Hz, 2H), 2.14 (br d, J = 11.9 Hz, 2H), 1.65-1.54 (m, 2H),1.53-1.43 (m, 2H), 1.33 (t, J = 7.5 Hz, 3H) 30

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- hydroxyquinazolin-6-yl)-3- methylphenyl)-2- chloro-N- methylbenzene- sulfonamide M + H⁺ =552.2 δ 8.99 (s, 1H), 8.51 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.68-7.53(m, 2H), 7.43 (t, J = 7.0 Hz, 1H), 7.22-7.06 (m, 4H), 7.01 (s, 1H), 4.09(br s, 1H), 3.42 (s, 3H), 3.15 (br t, J = 11.6 Hz, 1H), 2.30-2.20 (m,5H), 2.12 (br d, J = 12.7 Hz, 2H), 1.73-1.55 (m, 2H), 1.53-1.35 (m, 2H).31

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-3- methylphenyl)-2- chloro-N- methylbenzene- sulfonamide M + H⁺ =564.2 δ 8.98 (s, 1H), 8.51 (br s, 1H), 7.91 (d, J = 7.9 Hz, 1H),7.65-7.55 (m, 2H), 7.49-7.39 (m, 3H), 7.19-7.14 (m, 2H), 7.12-7.07 (m,1H), 3.98 (br t, J = 11.0 Hz, 1H), 3.42 (d, J = 1.8 Hz, 3H), 3.17 (br t,J = 11.4 Hz, 1H), 3.06 (q, J = 7.3 Hz, 2H), 2.32 (br d, J = 11.8 Hz,2H), 2.20 (s, 3H), 2.15 (br d, J = 12.3 Hz, 2H), 1.69- 1.43 (m, 4H),1.37- 1.28 (m, 3H). 32

N-(6-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)pyridazin-3- yl)-2- chlorobenzene- sulfonamide Calc'd forC₂₆H₂₉ClN₇O₂S: 538.2; Found: 538.2 δ 9.03 (s, 1H), 8.53 (br s, 1H),8.24-8.18 (m, 2H), 8.15 (d, J = 1.8 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H),7.95 (d, J = 10.1 Hz, 1H), 7.56-7.43 (m, 3H), 4.03-3.91 (m, 1H),3.23-3.11 (m, 1H), 3.06 (q, J = 7.5 Hz, 2H), 2.30 (br d, J = 10.1 Hz,2H), 2.14 (br d, J = 11.8 Hz, 2H), 1.67- 1.43 (m, 4H), 1.33 (t, J = 7.5Hz, 3H) 33

N-(2-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)pyrimidin-5- yl)-2- chlorobenzene- sulfonamide Calc'd forC₂₆H₂₉ClN₇O₂S: 538.2; Found: 538.1 δ 9.06 (s, 1H), 8.61 (s, 2H),8.55-8.43 (m, 3H), 8.20-8.12 (m, 1H), 7.66-7.54 (m, 2H), 7.54-7.45 (m,1H), 4.06-3.95 (m, 1H), 3.24-3.14 (m, 1H), 3.09 (q, J = 7.5 Hz, 2H),2.33 (br d, J = 12.5 Hz, 2H), 2.16 (br d, J = 10.8 Hz, 2H), 1.72- 1.42(m, 4H), 1.36 (t, J = 7.5 Hz, 3H) 34

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-3- ethylphenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 564.2 δ8.95 (s, 1H), 8.56 (br s, 1H), 8.14-8.06 (m, 1H), 7.60-7.52 (m, 2H),7.45 (m, 1H), 7.40 (d, J = 2.9 Hz, 2H), 7.11 (d, J = 1.8 Hz, 1H), 7.08-6.99 (m, 2H), 4.03- 3.85 (m, 1H), 3.16- 2.97 (m, 3H), 2.51 (q, J = 7.5Hz, 2H), 2.30 (br d, J = 10.6 Hz, 2H), 2.12 (br d, J = 12.1 Hz, 2H),1.62-1.42 (m, 4H), 1.30 (t, J = 7.5 Hz, 3H), 0.98 (t, J = 7.5 Hz, 3H) 35

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-3- fluorophenyl)-2- chlorobenzene- sulfonamide Calc'd forC₂₈H₃₀ClFN₅O₂S: 554.2; Found: 554.1 δ 8.97 (br d, J = 3.1 Hz, 1H), 8.55(br s, 1H), 8.15 (br dd, J = 2.6, 7.5 Hz, 1H), 7.64 (br s, 2H), 7.57 (brd, J = 3.1 Hz, 2H), 7.51-7.43 (m, 1H), 7.37 (dt, J = 3.5, 8.6 Hz, 1H),7.07-6.97 (m, 2H), 4.02-3.90 (m, 1H), 3.20-3.11 (m, 1H), 3.04 (br dd, J= 3.1, 7.3 Hz, 2H), 2.30 (br d, J = 11.2 Hz, 2H), 2.13 (br d, J = 11.2Hz, 2H), 1.66-1.40 (m, 4H), 1.31 (dt, J = 3.6, 7.3 Hz, 3H) 36

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- methoxyquinazolin-6-yl)-3- methylphenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 552.1 δ8.98 (s, 1H), 8.47 (s, 1H), 8.15-8.04 (m, 1H), 7.58-7.52 (m, 2H), 7.44(ddd, J = 2.6, 5.9, 8.1 Hz, 1H), 7.16 (d, J = 1.8 Hz, 1H), 7.12- 7.03(m, 4H), 4.05 (br t, J = 11.2 Hz, 1H), 3.95 (s, 3H), 3.14 (ddd, J = 3.9,7.7, 11.6 Hz, 1H), 2.27-2.17 (m, 5H), 2.11 (br d, J = 11.4 Hz, 2H),1.67-1.53 (m, 2H), 1.52-1.38 (m, 2H) 37

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-6- methoxypyridin- 2-yl)-2- chlorobenzene- sulfonamide M + H⁺ =567.2 δ 8.95 (s, 1 H), 8.54 (br s, 1 H), 8.31 (d, J = 7.72 Hz, 1 H),7.65 (t, J = 7.50 Hz, 3 H), 7.56- 7.60 (m, 2 H), 7.48- 7.54 (m, 1 H),6.63 (d, J = 7.94 Hz, 1 H), 3.91- 4.01 (m, 1 H), 3.65 (s, 3 H),3.10-3.21 (m, 1 H), 3.03 (q, J = 7.35 Hz, 2 H), 2.30 (br d, J = 12.13Hz, 2 H), 2.13 (br d, J = 12.13 Hz, 2 H), 1.44- 1.65 (m, 4 H), 1.30 (t,J = 7.50 Hz, 3 H) 38

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-4- methylthiazol-2- yl)-2- chlorobenzene- sulfonamide M + H⁺ =557.2 δ 9.02 (s, 1 H) 8.52 (br s, 1 H) 8.15 (d, J = 7.06 Hz, 1 H) 7.64(s, 1 H) 7.51-7.59 (m, 3 H) 7.43-7.49 (m, 1 H) 3.92-4.04 (m, 1 H)3.02-3.21 (m, 3 H) 2.30 (s, 5 H) 2.14 (br d, J = 12.13 Hz, 2 H) 1.44-1.64 (m, 4 H) 1.33 (t, J = 7.50 Hz, 3 H) 39

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)pyrimidin-2- yl)-2- chlorobenzene- sulfonamide M + H⁺ = 538.1 δ9.02 (br s, 1H), 8.51 (br s, 2H), 8.19 (s, 1H), 8.04 (br s, 1H), 7.78(br d, J = 6.8 Hz, 2H), 7.36 (br s, 4H), 3.78 (br s, 1H), 3.03 (br s,1H), 2.94 (q, J = 7.4 Hz, 2H), 2.09 (br s, 2H), 1.99 (br d, J = 10.8 Hz,2H), 1.52 (br s, 2H), 1.42- 1.30 (m, 2H), 1.23 (t, J = 7.4 Hz, 3H) 40

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- isopropylquinazolin-6-yl)-1-methyl- 1H-pyrazol-3-yl)- 2- chlorobenzene- sulfonamide M + H⁺ =554.2 δ 9.01 (s, 1H), 8.53 (br s, 1H), 8.12-8.07 (m, 1H), 7.60 (dd, J =1.8, 10.5 Hz, 2H), 7.57- 7.54 (m, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.47-7.41 (m, 1H), 6.09 (s, 1H), 4.03-3.87 (m, 2H), 3.71 (s, 3H), 3.17 (br t,J = 11.4 Hz, 1H), 2.30 (br d, J = 11.8 Hz, 2H), 2.14 (br d, J = 11.0 Hz,2H), 1.68-1.41 (m, 5H), 1.34 (d, J = 7.0 Hz, 6H) 41

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)thiazol-2-yl)- 2- chlorobenzene- sulfonamide M + H⁺ = 543.1 δ 8.98(s, 1H), 8.51 (br s, 1H), 8.17 (d, J = 7.0 Hz, 1H), 7.73 (s, 1H), 7.65(s, 1H), 7.58-7.40 (m, 4H), 4.01-3.89 (m, 1H), 3.19-2.98 (m, 3H), 2.30(br d, J = 12.3 Hz, 2H), 2.13 (br d, J = 13.2 Hz, 2H), 1.66- 1.41 (m,4H), 1.33 (t, J = 7.5 Hz, 3H) 42

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-2-fluoro-5- methoxyphenyl)- 2- chlorobenzene- sulfonamide M + H⁺ =584.2 δ 8.95 (s, 1 H), 8.55 (br s, 1 H), 8.09 (d, J = 7.28 Hz, 1 H),7.54-7.67 (m, 4 H), 7.41-7.47 (m, 1 H), 7.05-7.11 (m, 2 H), 3.96 (br t,J = 11.36 Hz, 1 H), 3.70 (s, 3 H), 3.10- 3.19 (m, 1 H), 3.03 (q, J =7.72 Hz, 2 H), 2.30 (br d, J = 12.57 Hz, 2 H), 2.13 (br d, J = 11.47 Hz,2 H), 1.42-1.65 (m, 4 H), 1.31 (t, J = 7.39 Hz, 3 H) 43

N-(1-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-1H-pyrazol- 4-yl)-2- chlorobenzene- sulfonamide M + H⁺ = 526.0 δ9.09 (br s, 1H), 8.40 (br s, 1H), 8.05 (s, 1H), 8.01-7.95 (m, 2H), 7.88(d, J = 2.3 Hz, 1H), 7.65-7.47 (m, 2H), 7.44-7.34 (m, 2H), 3.77 (br s,1H), 3.05- 2.90 (m, 3H), 2.12- 1.96 (m, 4H), 1.49- 1.24 (m, 7H) 44

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)isoxazol-3- yl)-2- chlorobenzene- sulfonamide M + H⁺ = 527.1 δ 9.13(br s, 1H), 8.39 (br s, 1H), 8.06-7.90 (m, 2H), 7.79 (d, J = 1.6 Hz,1H), 7.55 (br s, 1H), 7.46-7.40 (m, 1H), 7.39-7.29 (m, 2H), 6.53 (s,1H), 3.80 (br s, 1H), 2.98 (q, J = 7.4 Hz, 3H), 2.17-1.94 (m, 4H),1.53-1.32 (m, 4H), 1.31-1.22 (m, 3H). 45

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- methoxyquinazolin-6-yl)-1-methyl- 1H-pyrazol-3-yl)- 2- chlorobenzene- sulfonamide M + H⁺ =542.2 δ 9.05 (br s, 1H), 8.33 (br s, 2H), 8.02 (d, J = 7.7 Hz, 1H),7.60-7.34 (m, 5H), 7.10 (br s, 1H), 6.02 (s, 1H), 3.89 (br s, 4H), 3.68(s, 3H), 2.96 (br s, 1H), 1.97 (br s, 4H), 1.49-1.26 (m, 4H). 46

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-4- methoxypyrimidin- 2-yl)-2- chlorobenzene- sulfonamide M + H⁺ =568.2 δ 8.98 (s, 1 H), 8.50 (br s, 1 H), 8.33 (d, J = 7.94 Hz, 1 H),8.14 (s, 1 H), 7.61-7.68 (m, 2 H), 7.48-7.58 (m, 3 H), 3.91-4.02 (m, 1H), 3.71 (s, 3 H), 3.11-3.23 (m, 1 H), 3.04 (q, J = 7.72 Hz, 2 H), 2.31(br d, J = 11.69 Hz, 2 H), 2.14 (br d, J = 11.47 Hz, 2 H), 1.43-1.66 (m,4 H), 1.31 (t, J = 7.50 Hz, 3 H) 47

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- propylquinazolin-6-yl)-1-methyl- 1H-pyrazol-3-yl)- 2- chlorobenzene- sulfonamide M + H⁺ =554.2 δ 9.02 (s, 1H), 8.48 (br s, 1H), 8.09 (dd, J = 1.3, 7.9 Hz, 1H),7.62 (d, J = 2.0 Hz, 1H), 7.61-7.54 (m, 2H), 7.52 (d, J = 2.0 Hz, 1H),7.44 (ddd, J = 1.9, 6.7, 8.1 Hz, 1H), 6.10 (s, 1H), 4.00-3.90 (m, 1H),3.72 (s, 3H), 3.23-3.12 (m, 1H), 3.05-2.96 (m, 2H), 2.32 (br d, J = 11.7Hz, 2H), 2.15 (br d, J = 11.2 Hz, 2H), 1.76 (qd, J = 7.4, 15.0 Hz, 2H),1.67- 1.41 (m, 4H), 1.01 (t, J = 7.3 Hz, 3H) 48

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)quinazolin- 6-yl)-3-fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 526.1 δ 9.06 (s,1H), 8.50 (br s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.91-7.80 (m, 2H),7.62-7.56 (m, 3H), 7.53-7.48 (m, 1H), 7.46-7.40 (m, 1H), 7.11-7.02 (m,2H), 4.04-3.93 (m, 1H), 3.22-3.11 (m, 1H), 2.25 (br d, J = 13.0 Hz, 2H),2.14 (br d, J = 11.9 Hz, 2H), 1.71- 1.40 (m, 4H) 49

N-(6-(2-(((1r,4r)- 4- aminocyclohexyl) amino)quinazolin-6-yl)pyridazin-3- yl)-2- chlorobenzene- sulfonamide M + H⁺ = 510.1 δ9.13 (s, 1H), 8.42 (br s, 1H), 8.37-8.27 (m, 3H), 8.23 (d, J = 6.7 Hz,1H), 8.07 (d, J = 10.0 Hz, 1H), 7.68-7.44 (m, 4H), 4.01 (br t, J = 11.2Hz, 1H), 3.24-3.11 (m, 1H), 2.33-2.10 (m, 4H), 1.72-1.44 (m, 4H) 50

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)quinazolin- 6-yl)-2-fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 526.1 δ 9.08 (br s,1H), 8.25 (s, 1H), 8.00-7.91 (m, 3H), 7.50-7.29 (m, 5H), 7.24-7.12 (m,2H), 3.81 (br d, J = 8.1 Hz, 1H), 3.03 (br d, J = 10.9 Hz, 1H), 2.11-1.92 (m, 4H), 1.53- 1.29 (m, 4H) 51

N-(6-(2-(((1r,4r)- 4- aminocyclohexyl) amino)quinazolin- 6-yl)-5-fluoropyridin-3- yl)-2- chlorobenzene- sulfonamide M + H⁺ = 527.1 δ 9.08(s, 1H), 8.45 (br s, 1H), 8.29 (s, 1H), 8.24- 8.15 (m, 3H), 7.64- 7.55(m, 3H), 7.54- 7.45 (m, 2H), 3.98 (br t, J = 11.4 Hz, 1H), 3.21- 3.09(m, 1H), 2.24 (br d, J = 11.7 Hz, 2H), 2.13 (br d, J = 11.7 Hz, 2H),1.71-1.41 (m, 4H) 52

N-(6-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-5- fluoropyridin-3- yl)-2- chlorobenzene- sulfonamide M + H⁺ =555.2 δ 9.02 (s, 1H), 8.51 (br s, 1H), 8.28 (s, 1H), 8.19 (d, J = 7.9Hz, 1H), 8.05 (br d, J = 7.5 Hz, 2H), 7.64-7.56 (m, 2H), 7.54-7.42 (m,2H), 3.99 (br t, J = 11.0 Hz, 1H), 3.18 (br t, J = 11.5 Hz, 1H), 3.08(q, J = 7.5 Hz, 2H), 2.32 (br d, J = 11.2 Hz, 2H), 2.15 (br d, J = 11.2Hz, 2H), 1.70- 1.43 (m, 4H), 1.34 (t, J = 7.4 Hz, 3H). 53

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)quinazolin- 6-yl)-2,5-difluorophenyl)- 2- chlorobenzene- sulfonamide M + H⁺ = 544.1 δ 9.10 (brs, 1 H), 8.17 (br s, 1 H), 7.97 (dd, J = 7.28, 1.98 Hz, 1 H), 7.85- 7.89(m, 1 H), 7.80 (br d, J = 8.82 Hz, 1 H), 7.36-7.47 (m, 4 H), 7.13-7.23(m, 1 H), 6.98 (br dd, J = 14.33, 7.50 Hz, 1 H), 3.80 (br s, 1 H), 3.03(br s, 1 H), 1.88-2.12 (m, 4 H), 1.22-1.57 (m, 4 H) 54

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)quinazolin- 6-yl)-3-fluoropyridin-2- yl)-2- chlorobenzene- sulfonamide M + H⁺ = 527.1 δ 9.10(s, 1H), 8.29 (br dd, J = 2.1, 5.6 Hz, 3H), 8.23 (d, J = 1.8 Hz, 1H),8.02-7.91 (m, 2H), 7.63-7.57 (m, 2H), 7.57-7.51 (m, 1H), 3.99 (br t, J =11.2 Hz, 1H), 3.21-3.09 (m, 1H), 2.25 (br d, J = 12.3 Hz, 2H), 2.14 (brd, J = 12.0 Hz, 2H), 1.71- 1.41 (m, 4H) 55

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-3- fluoropyridin-2- yl)-2- chlorobenzene- sulfonamide M + H⁺ =555.2 ) δ 9.00 (s, 1H), 8.49 (br s, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.16(s, 1H), 7.85 (br d, J = 11.6 Hz, 1H), 7.76 (br s, 2H), 7.57-7.51 (m,2H), 7.51-7.44 (m, 1H), 4.01-3.87 (m, 1H), 3.22-3.12 (m, 1H), 3.06 (q, J= 7.5 Hz, 2H), 2.30 (br d, J = 11.5 Hz, 2H), 2.14 (br d, J = 12.2 Hz,2H), 1.72-1.41 (m, 4H), 1.32 (t, J = 7.5 Hz, 3H) 56

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)quinazolin- 6-yl)-2,3-difluorophenyl)- 2- chlorobenzene- sulfonamide M + H⁺ = 544.1 δ 9.06 (s,1H), 8.42 (br s, 1H), 8.08-8.02 (m, 1H), 7.89 (s, 1H), 7.83 (br d, J =9.0 Hz, 1H), 7.65-7.55 (m, 3H), 7.48-7.41 (m, 1H), 7.32-7.20 (m, 2H),4.04-3.91 (m, 1H), 3.21-3.08 (m, 1H), 2.23 (br d, J = 11.2 Hz, 2H), 2.12(br d, J = 12.3 Hz, 2H), 1.68-1.38 (m, 4H) 57

N-(4-(3-(((1r,4r)- 4- aminocyclohexyl) amino)isoquinolin- 7-yl)-2-fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 525.1 δ 8.83 (s,1H), 8.46 (br s, 1H), 8.05-7.93 (m, 2H), 7.71 (dd, J = 1.9, 8.7 Hz, 1H),7.62-7.53 (m, 3H), 7.50-7.44 (m, 1H), 7.44-7.37 (m, 3H), 6.68 (s, 1H),3.68 (tt, J = 3.8, 11.2 Hz, 1H), 3.16 (tt, J = 3.9, 11.7 Hz, 1H), 2.29-2.18 (m, 2H), 2.12 (br d, J = 12.1 Hz, 2H), 1.61 (dq, J = 3.1, 12.6 Hz,2H), 1.48-1.33 (m, 2H) 58

(S)-2-amino-N- ((1r,4S)-4-((6-(4- ((2- chlorophenyl) sulfonamido)-3-fluorophenyl)-8- ethylquinazolin- 2- yl)amino)cyclo- hexyl)-3-methylbutanamide M + H⁺ = 653.2 δ 8.98 (s, 1H), 8.54 (br s, 1H), 8.02(dd, J = 1.2, 7.9 Hz, 1H), 7.73 (br d, J = 4.3 Hz, 2H), 7.64- 7.52 (m,2H), 7.50- 7.44 (m, 1H), 7.44- 7.34 (m, 3H), 3.96 (br s, 1H), 3.80 (brs, 1H), 3.52 (br d, J = 6.0 Hz, 1H), 3.06 (q, J = 7.3 Hz, 2H), 2.24 (brs, 2H), 2.15 (br dd, J = 6.6, 13.2 Hz, 1H), 2.05 (br s, 2H), 1.50 (br d,J = 8.6 Hz, 4H), 1.33 (br t, J = 7.4 Hz, 3H), 1.07 (br dd, J = 4.0, 6.7Hz, 6H). 59

N-((1r,4r)-4-((6- (4-((2- chlorophenyl) sulfonamido)-3- fluorophenyl)-8-ethylquinazolin- 2- yl)amino)cyclo- hexyl)acetamide M + H+ = 596.1 δ8.98 (s, 1H), 8.00 (dd, J = 1.5, 7.9 Hz, 1H), 7.75 (s, 2H), 7.63-7.52(m, 2H), 7.50-7.44 (m, 1H), 7.43-7.36 (m, 3H), 3.98-3.88 (m, 1H), 3.68(br d, J = 15.7 Hz, 1H), 3.06 (q, J = 7.4 Hz, 2H), 2.20 (br d, J = 11.7Hz, 2H), 1.99 (br d, J = 9.3 Hz, 2H), 1.93 (s, 3H), 1.50-1.37 (m, 4H),1.33 (t, J = 7.5 Hz, 3H). 60

2-chloro-N-(4-(8- ethyl-2-(((1r,4r)- 4- (methylamino) cyclohexyl)amino)quinazolin-6-yl)- 2-fluorophenyl) benzenesulfonamide M + H⁺ = 568.2 δ9.05 (br s, 1H), 8.25 (br s, 1H), 7.95 (dd, J = 2.0, 7.5 Hz, 1H), 7.80(d, J = 1.3 Hz, 2H), 7.47- 7.43 (m, 1H), 7.41- 7.30 (m, 4H), 7.20- 7.13(m, 2H), 3.79 (br s, 1H), 2.98 (q, J = 7.6 Hz, 2H), 2.91 (br s, 1H),2.55 (s, 3H), 2.09 (br d, J = 9.3 Hz, 4H), 1.46- 1.33 (m, 4H), 1.28 (t,J = 7.4 Hz, 3H) 62

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)quinazolin- 6-yl)-3,5-difluorophenyl)- 2- chlorobenzene- sulfonamide M + H⁺ = 544.1 δ 8.93 (s,1H), 8.42 (br s, 1H), 8.18-8.04 (m, 1H), 7.67 (s, 1H), 7.61- 7.55 (m,1H), 7.53- 7.50 (m, 2H), 7.48- 7.39 (m, 2H), 6.82- 6.75 (m, 2H), 3.96-3.83 (m, 1H), 3.06 (tt, J = 3.9, 11.6 Hz, 1H), 2.15 (br d, J = 11.0 Hz,2H), 2.03 (br d, J = 12.2 Hz, 2H), 1.59-1.46 (m, 2H), 1.44-1.31 (m, 2H).63

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-2,6- difluorophenyl)- 2- chlorobenzene- sulfonamide M + H⁺ = 572.2δ 9.04 (br s, 1H), 8.43 (br s, 2H), 7.95 (br d, J = 7.8 Hz, 1H), 7.82(br d, J = 15.6 Hz, 2H), 7.70-7.57 (m, 2H), 7.43 (br t, J = 7.4 Hz, 1H),7.33 (br d, J = 8.9 Hz, 2H), 3.99 (br s, 1H), 3.25-3.03 (m, 3H), 2.33(br d, J = 10.3 Hz, 2H), 2.17 (br d, J = 9.8 Hz, 2H), 1.70-1.46 (m, 4H),1.36 (br t, J = 7.2 Hz, 3H). 65

N-(6-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-5- methoxypyridazin- 3-yl)-2- chlorobenzene- sulfonamide M + H⁺ =568.2 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 9.04 (s, 1H), 8.52 (br s,1H), 8.24 (dd, J = 1.5, 7.7 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.98-7.91(m, 1H), 7.61-7.45 (m, 3H), 7.34 (s, 1H), 4.05- 3.95 (m, 4H), 3.19 (brt, J = 11.4 Hz, 1H), 3.07 (q, J = 7.5 Hz, 2H), 2.32 (br d, J = 11.1 Hz,2H), 2.17 (br d, J = 11.4 Hz, 2H), 1.70-1.43 (m, 4H), 1.39-1.27 (m, 3H)66

N-(6-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-4- methoxypyridazin- 3-yl)-2- chlorobenzene- sulfonamide M + H⁺ =568.2 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 8.96 (s, 1H), 8.35 (br s,1H), 8.19-8.05 (m, 3H), 7.52-7.32 (m, 4H), 4.03-3.79 (m, 4H), 3.14-2.93(m, 3H), 2.21 (br d, J = 11.0 Hz, 2H), 2.05 (br d, J = 10.6 Hz, 2H),1.61-1.33 (m, 4H), 1.25 (t, J = 7.5 Hz, 3H) 67

N-(6-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-5- methylpyridazin- 3-yl)-2- chlorobenzene- sulfonamide M + H⁺ =552.1 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 9.04 (s, 1H), 8.56 (br s,1H), 8.22 (br d, J = 7.3 Hz, 1H), 7.75 (s, 1H), 7.68 (br s, 2H),7.57-7.41 (m, 3H), 3.98 (br t, J = 11.0 Hz, 1H), 3.22- 3.01 (m, 3H),2.41- 2.25 (m, 5H), 2.14 (br d, J = 11.5 Hz, 2H), 1.70- 1.42 (m, 4H),1.33 (br t, J = 7.5 Hz, 3H) 68

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)quinazolin- 6-yl)-4-methylpyrimidin- 2-yl)-2- chlorobenzene- sulfonamide M + H⁺ = 524 δ =9.04 (s, 1H), 8.50 (br s, 1H), 8.31 (dd, J = 1.3, 7.7 Hz, 1H), 8.22 (s,1H), 7.71-7.61 (m, 2H), 7.60-7.47 (m, 4H), 4.03-3.90 (m, 1H), 3.15 (tt,J = 3.9, 11.6 Hz, 1H), 2.29 (s, 3H), 2.23 (br d, J = 11.5 Hz, 2H), 2.12(br d, J = 12.6 Hz, 2H), 1.66- 1.40 (m, 4H). 69

2-chloro-N-(4-(2- (((1r,4r)-4- (dimethylamino) cyclohexyl)amino)- 8-ethylquinazolin- 6-yl)-2- fluorophenyl) benzenesulfonamide M + H⁺ =582.2 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 9.01 (s, 1H), 8.56 (br s,1H), 8.03 (d, J = 7.7 Hz, 1H), 7.77 (br s, 2H), 7.66- 7.54 (m, 2H),7.51- 7.34 (m, 4H), 3.98 (br t, J = 11.6 Hz, 1H), 3.22- 3.02 (m, 3H),2.82 (s, 6H), 2.39 (br d, J = 12.0 Hz, 2H), 2.18 (br d, J = 12.1 Hz,2H), 1.78- 1.63 (m, 2H), 1.57- 1.41 (m, 2H), 1.34 (t, J = 7.5 Hz, 2H) 70

N-(4-(2- (((1R,3R,4S)-4- amino-3- methylcyclohexyl) amino)-8-ethylquinazolin- 6-yl)-2- fluorophenyl)-2- chlorobenzene- sulfonamideM + H⁺ = 568.2 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 9.04 (s, 1H), 8.55(br s, 1H), 8.03 (dd, J = 1.3, 7.9 Hz, 1H), 7.79 (s, 2H), 7.65-7.55 (m,2H), 7.52-7.32 (m, 4H), 4.07 (ddd, J = 3.9, 7.6, 11.4 Hz, 1H), 3.46 (brs, 1H), 3.16-3.02 (m, 2H), 2.27-2.04 (m, 4H), 2.03-1.88 (m, 1H),1.52-1.26 (m, 5H), 1.11 (d, J = 6.8 Hz, 3H) 71

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-2-fluoro-3- methylphenyl)-2- chlorobenzene- sulfonamide M + H⁺ =568.0 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 8.98 (s, 1H), 8.53 (br s,1H), 8.03 (dd, J = 1.2, 8.0 Hz, 1H), 7.66-7.53 (m, 2H), 7.49-7.39 (m,3H), 7.28 (t, J = 8.2 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.04-3.91 (m,1H), 3.23-3.12 (m, 1H), 3.06 (q, J = 7.5 Hz, 2H), 2.32 (br d, J = 11.9Hz, 2H), 2.20-2.05 (m, 5H), 1.67-1.42 (m, 4H), 1.31 (t, J = 7.4 Hz, 3H).72

N-(4-(2- (((1R,3S)-3- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-2- fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 554.3(LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 9.00 (s, 1H), 8.55 (br s, 1H),8.02 (dd, J = 1.4, 8.0 Hz, 1H), 7.79-7.71 (m, 2H), 7.64-7.50 (m, 2H),7.49-7.27 (m, 4H), 4.08 (ddd, J = 4.0, 7.7, 11.5 Hz, 1H), 3.23 (ddd, J =3.9, 8.2, 11.8 Hz, 1H), 3.17-2.97 (m, 2H), 2.52 (br d, J = 11.2 Hz, 1H),2.27-1.88 (m, 3H), 1.66-1.46 (m, 1H), 1.43-1.26 (m, 6H) 73

(S)-2-chloro-N- (4-(8-ethyl-2- (piperidin-3- ylamino)quinazolin-6-yl)-2- fluorophenyl) benzenesulfonamide M + H⁺ = 540.2 (LCMS) ¹H NMR(400 MHz, METHANOL-d₄) δ 9.08 (s, 1H), 8.51 (br s, 1H), 8.01 (dd, J =1.3, 7.9 Hz, 1H), 7.81 (s, 2H), 7.66-7.34 (m, 6H), 4.45-4.24 (m, 1H),3.66 (br dd, J = 3.3, 12.1 Hz, 1H), 3.20-2.97 (m, 4H), 2.24-2.06 (m,2H), 1.97-1.76 (m, 2H), 1.34 (t, J = 7.5 Hz, 3H) 74

N-(4-(2- (((1R,3R,4R)-4- amino-3- methylcyclohexyl) amino)-8-ethylquinazolin- 6-yl)-2- fluorophenyl)-2- chlorobenzene- sulfonamideM + H⁺ = 568.2 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 9.04 (s, 1H), 8.56(br s, 1H), 8.09-7.99 (m, 1H), 7.80 (s, 2H), 7.66-7.54 (m, 2H),7.54-7.38 (m, 4H), 4.05 (br t, J = 11.6 Hz, 1H), 3.17-3.04 (m, 2H), 2.83(dt, J = 3.9, 10.9 Hz, 1H), 2.37- 2.25 (m, 2H), 2.16 (br dd, J = 3.5,12.3 Hz, 1H), 1.76 (br s, 1H), 1.67-1.41 (m, 2H), 1.38-1.19 (m, 4H),1.14 (d, J = 6.5 Hz, 3H). 75

N-(4-(2- (((1R,3S)-3- aminocyclohexyl) amino)quinazolin- 6-yl)-2-fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 526.1 (LCMS) ¹H NMR(400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.22 (br s, 1H), 7.98-7.88 (m, 3H),7.46-7.28 (m, 5H), 7.18-7.11 (m, 2H), 3.93 (brs, 1H), 2.27 (br s, 1H),1.91 (br s, 2H), 1.79 (br d, J = 12.8 Hz, 1H), 1.49-1.11 (m, 4H) 76

(S)-2-chloro-N- (2-fluoro-4-(2- (piperidin-3- ylamino)quinazolin- 6-yl)phenyl)benzene- sulfonamide M + H⁺ = 512.1 (LCMS) ¹H NMR (400 MHz,METHANOL-d₄) δ 9.11 (s, 1H), 8.56 (br s, 1H), 8.06-7.91 (m, 3H),7.62-7.52 (m, 3H), 7.50-7.44 (m, 1H), 7.44-7.38 (m, 3H), 4.42-4.24 (m,1H), 3.60 (br dd, J = 3.1, 12.1 Hz, 1H), 3.30 (br s, 1H), 3.04-2.94 (m,2H), 2.24-2.01 (m, 2H), 1.95-1.67 (m, 2H). 77

N-(4-(2- (((1R,3R)-3- aminocyclopentyl) amino)quinazolin- 6-yl)-2-fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 512.1 (LCMS) ¹H NMR(400 MHz, METHANOL-d₄) δ 9.05 (s, 1H), 8.52 (br s, 1H), 8.00 (dd, J =1.3, 7.9 Hz, 1H), 7.95-7.88 (m, 2H), 7.61-7.51 (m, 3H), 7.50-7.43 (m,1H), 7.43-7.34 (m, 3H), 4.66-4.56 (m, 1H), 3.81 (quin, J = 6.9 Hz, 1H),2.40-2.25 (m, 2H), 2.15 (t, J = 6.9 Hz, 2H), 1.84-1.66 (m, 2H). 78

N-(4-(2- (((1R,3R)-3- aminocyclopentyl) amino)-8- ethylquinazolin-6-yl)-2- fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 540.1(LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 9.00 (s, 1H), 8.48 (br s, 1H),8.00 (dd, J = 1.3, 7.9 Hz, 1H), 7.75 (s, 2H), 7.61-7.51 (m, 2H),7.49-7.34 (m, 4H), 4.60 (quin, J = 6.6 Hz, 1H), 3.80 (quin, J = 7.1 Hz,1H), 3.08 (q, J = 7.4 Hz, 2H), 2.41-2.28 (m, 2H), 2.27-2.12 (m, 2H),1.88-1.67 (m, 2H), 1.32 (t, J = 7.5 Hz, 3H) 79

N-(4-(2- (((1R,3S)-3- aminocyclopentyl) amino)-8- ethylquinazolin-6-yl)-2- fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 540.1(LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 9.05 (s, 1H), 8.56 (br s, 1H),8.03 (d, J = 7.9 Hz, 1H), 7.83-7.78 (m, 2H), 7.66-7.53 (m, 2H),7.52-7.37 (m, 4H), 4.48 (quin, J = 7.0 Hz, 1H), 3.72 (quin, J = 7.2 Hz,1H), 3.11 (q, J = 7.4 Hz, 2H), 2.85-2.71 (m, 1H), 2.33-2.14 (m, 2H),2.01-1.81 (m, 2H), 1.76-1.64 (m, 1H), 1.39-1.31 (m, 3H) 80

N-(4-(2- (((1R,3S)-3- aminocyclopentyl) amino)quinazolin- 6-yl)-2-fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 512.1 (LCMS) ¹H NMR(400 MHz, METHANOL-d₄) δ 9.11 (s, 1H), 8.54 (br s, 1H), 8.08-7.95 (m,3H), 7.67-7.37 (m, 7H), 4.55-4.39 (m, 1H), 3.80-3.66 (m, 1H), 2.77-2.61(m, 1H), 2.29-2.11 (m, 2H), 2.05-1.83 (m, 2H), 1.77-1.63 (m, 1H) 81

N-(4-(2-((4- aminobicyclo[2.2.2] octan-1- yl)amino)quinazolin- 6-yl)-2-fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 552.1 (LCMS) ¹H NMR(400 MHz, METHANOL-d₄) δ 9.02 (s, 1H), 8.44 (br s, 1H), 8.00 (d, J = 7.9Hz, 1H), 7.93 (br s, 2H), 7.62- 7.52 (m, 3H), 7.51- 7.44 (m, 1H), 7.41(br d, J = 8.2 Hz, 3H), 2.35- 2.27 (m, 6H), 1.99- 1.92 (m, 6H) 82

N-(4-(2-(((2r,5r)- 5- aminooctahydro- pentalen-2- yl)amino)-8-ethylquinazolin- 6-yl)-2- fluorophenyl)-2- chlorobenzene- sulfonamideM + H⁺ = 580.1 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 8.91 (s, 1H), 8.40(br s, 1H), 7.91 (dd, J = 1.3, 7.9 Hz, 1H), 7.68 (s, 2H), 7.54-7.44 (m,2H), 7.41-7.25 (m, 4H), 4.50-4.41 (m, 2H), 3.00 (q, J = 7.4 Hz, 2H),2.68-2.55 (m, 2H), 2.36-2.22 (m, 2H), 1.97 (br dd, J = 5.9, 12.5 Hz,2H), 1.66 (td, J = 9.0, 12.5 Hz, 2H), 1.38- 1.21 (m, 5H) 83

N-(4-(2-(((2r,5r)- 5- aminooctahydro- pentalen-2- yl)amino)-8-ethylquinazolin- 6-yl)-2- fluorophenyl)-2- chlorobenzene- sulfonamideM + H⁺ = 580.2 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 8.99 (s, 1H), 8.54(br s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.76 (s, 2H), 7.62-7.52 (m, 2H),7.49-7.36 (m, 4H), 4.38-4.17 (m, 1H), 3.83-3.66 (m, 1H), 3.13-3.00 (m,2H), 2.73 (br s, 2H), 2.55-2.46 (m, 2H), 1.94 (br dd, J = 6.4, 12.5 Hz,2H), 1.85-1.74 (m, 2H), 1.32 (t, J = 7.5 Hz, 3H), 1.28-1.21 (m, 2H) 84

N-(4-(2-(((2s,5s)- 5- aminooctahydro- pentalen-2- yl)amino)-8-ethylquinazolin- 6-yl)-2- fluorophenyl)-2- chlorobenzene- sulfonamideM + H⁺ = 580.1 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 8.99 (s, 1H), 8.48(br s, 1H), 8.00 (dd, J = 1.3, 7.9 Hz, 1H), 7.75 (s, 2H), 7.62-7.52 (m,2H), 7.50-7.36 (m, 4H), 4.50-4.38 (m, 1H), 3.57-3.45 (m, 1H), 3.06 (q, J= 7.6 Hz, 2H), 2.67-2.57 (m, 2H), 2.52 (br dd, J = 6.4, 12.5 Hz, 2H),2.44-2.33 (m, 2H), 1.59-1.39 (m, 4H), 1.32 (t, J = 7.5 Hz, 3H) 85

N-(4-(2-(((2s,5s)- 5- aminooctahydro- pentalen-2- yl)amino)quinazolin-6-yl)-2- fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 552.1(LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 9.06 (s, 1H), 8.47 (br s, 1H),8.06-7.89 (m, 3H), 7.64-7.53 (m, 3H), 7.52-7.36 (m, 4H), 4.52-4.38 (m,1H), 3.60-3.44 (m, 1H), 2.72-2.53 (m, 2H), 2.53-2.31 (m, 4H), 1.55-1.37(m, 4H). 86

N-(4-(2-((4- aminobicyclo[2.2.1] heptan-1- yl)amino)quinazolin- 6-yl)-2-fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 538.1 (LCMS) ¹H NMR(400 MHz, METHANOL-d₄) δ 9.06 (s, 1H), 8.59-8.47 (m, 1H), 8.08-7.87 (m,3H), 7.63-7.34 (m, 7H), 2.48-2.28 (m, 4H), 2.06-1.85 (m, 6H) 87

N-(4-(2-((4- aminobicyclo[2.2.2] octan-1- yl)amino)-8- ethylquinazolin-6-yl)-2- fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 580.2(LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 8.98 (s, 1H), 8.49 (br s, 1H),8.02 (dd, J = 1.4, 7.9 Hz, 1H), 7.77 (dd, J = 1.9, 12.2 Hz, 2H), 7.63-7.55 (m, 2H), 7.51- 7.38 (m, 4H), 3.10 (q, J = 7.5 Hz, 2H), 2.42- 2.32(m, 6H), 2.04- 1.94 (m, 6H), 1.36 (t, J = 7.5 Hz, 3H) 88

2-chloro-N-(4-(8- ethyl-2-(((1r,4r)- 4-(pyrrolidin-1-yl)cyclohexyl)amino) quinazolin-6- yl)-2- fluorophenyl)benzenesulfonamide M + H⁺ = 608.3 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ9.02 (s, 1H), 8.57 (br s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.79 (s, 2H),7.64-7.54 (m, 2H), 7.51-7.39 (m, 4H), 3.98 (br t, J = 11.4 Hz, 1H),3.33-3.29 (m, 4H), 3.12-3.01 (m, 3H), 2.44-2.24 (m, 4H), 2.07 (br s,4H), 1.73-1.59 (m, 2H), 1.54-1.42 (m, 2H), 1.35 (t, J = 7.5 Hz, 3H) 89

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)quinazolin- 6-yl)-1,3,4-thiadiazol-2-yl)- 2- chlorobenzene- sulfonamide M + H⁺ = 516.1 (LCMS) ¹HNMR (400 MHz, DMSO-d₆) δ 9.13 (br s, 1H), 8.19 (s, 1H), 8.10 (br d, J =9.3 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.96 (dd, J = 1.9, 7.6 Hz, 1H),7.50-7.31 (m, 5H), 3.80 (br d, J = 12.1 Hz, 1H), 2.98 (br s, 1H),2.05-1.90 (m, 4H), 1.48-1.27 (m, 4H). 90

N-(4-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-7- methylquinazolin-6-yl)-2- 4-fluorophenyl)-2- chlorobenzene- sulfonamide M + H⁺ = 540.3(LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 8.95 (s, 1H), 8.07 (dd, J = 1.6,7.8 Hz, 1H), 7.60- 7.47 (m, 3H), 7.43- 7.32 (m, 3H), 7.07- 6.94 (m, 2H),4.00- 3.89 (m, 1H), 3.0 2.93 (m, 1H), 2.34 (s, 3H), 2.23-2.16 (m, 2H),2.12-2.03 (m, 2H), 1.59-1.41 (m, 4H) 92

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-4- methoxypyridin- 2-yl)-2- chlorobenzene- sulfonamide M + H⁺ =567.1 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 8.99 (s, 1H), 8.40 (br s,1H), 8.31-8.21 (m, 1H), 7.84 (s, 1H), 7.66-7.45 (m, 5H), 6.83 (s, 1H),4.03-3.92 (m, 1H), 3.88 (s, 3H), 3.23-3.12 (m, 1H), 3.05 (q, J = 7.4 Hz,2H), 2.31 (br d, J = 12.3 Hz, 2H), 2.14 (br d, J = 12.1 Hz, 2H), 1.68-1.42 (m, 4H), 1.31 (t, J = 7.5 Hz, 3H) 93

N-(6-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-5- methoxypyridin- 3-yl)-2- chlorobenzene- sulfonamide M + H⁺ =567.2 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 8.98 (s, 1H), 8.48 (br s,1H), 8.20-8.12 (m, 1H), 8.06-7.91 (m, 3H), 7.64-7.54 (m, 2H), 7.49 (ddd,J = 2.6, 5.8, 8.0 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 4.02-3.92 (m, 1H),3.84 (s, 3H), 3.24-3.12 (m, 1H), 3.05 (q, J = 7.6 Hz, 2H), 2.30 (br d, J= 11.0 Hz, 2H), 2.14 (br d, J = 11.9 Hz, 2H), 1.66-1.41 (m, 4H), 1.32(t, J = 7.4 Hz, 3H) 94

N-(5-(2-(((1r,4r)- 4- aminocyclohexyl) amino)-8- ethylquinazolin-6-yl)-6- methylpyrazin-2- yl)-2- chlorobenzene- sulfonamide M + H⁺ =552.2 (LCMS) ¹H NMR (400 MHz, METHANOL-d₄) δ 9.00 (s, 1H), 8.50 (br s,1H), 8.30 (d, J = 7.3 Hz, 1H), 8.15 (s, 1H), 7.68 (s, 2H), 7.59-7.47 (m,3H), 4.03-3.92 (m, 1H), 3.22-3.12 (m, 1H), 3.06 (q, J = 7.5 Hz, 2H),2.37 (s, 3H), 2.30 (br d, J = 11.0 Hz, 2H), 2.14 (br d, J = 11.9 Hz,2H), 1.66-1.42 (m, 4H), 1.31 (t, J = 7.5 Hz, 3H)

Example 5: Synthesis ofN-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-ethylpyridazin-3-yl)-2-chlorobenzenesulfonamide(96)

Step 1

To a solution of 2-chlorobenzene-1-sulfonyl chloride (2.0 g, 9.5 mmol,1.3 mL) in THF (20.0 mL) was added NH3.H2O (3.3 g, 28.4 mmol, 3.7 mL,25% solution) at 0° C. The mixture was stirred at 0° C. for 10 min andthen warmed to 20° C. for 2 h. The reaction mixture was concentrated toafford 2-chlorobenzenesulfonamide (1.8 g, 9.4 mmol, 99.1% yield). 1H NMR(400 MHz, DMSO-d₆) δ 7.96 (dd, J=1.4, 7.8 Hz, 1H), 7.65-7.55 (m, 2H),7.54-7.34 (m, 7H).

Step 2

A mixture of 3,6-dichloro-4-ethylpyridazine (500 mg, 2.8 mmol),2-chlorobenzenesulfonamide (595 mg, 3.1 mmol), Cs₂CO₃ (2.7 g, 8.5 mmol),dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (132 mg, 282.4umol) and[2-(2-aminoethyl)phenyl]-chloro-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane(194 mg, 282.4 umol) in THF (30.0 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 80° C. for 12 h underN₂ atmosphere. The reaction was concentrated to give a residue. Theresidue was purified by column chromatography (SiO₂) to give a crudeproduct (280 mg). The crude product was purified by prep-HPLC (TFAcondition) to afford2-chloro-N-(6-chloro-5-ethylpyridazin-3-yl)benzenesulfonamide (20 mg,54.2 umol, 1.9% yield). ¹H NMR (400 MHz, METHANOL-d₄) δ 8.20 (d, J=7.7Hz, 1H), 7.64 (br s, 1H), 7.57-7.53 (m, 2H), 7.52-7.46 (m, 1H), 2.71 (q,J=7.5 Hz, 2H), 1.23 (t, J=7.4 Hz, 3H); and2-chloro-N-(6-chloro-4-ethylpyridazin-3-yl)benzenesulfonamide (100 mg,270.9 umol, 10.7% yield). ¹H NMR (400 MHz, METHANOL-d₄) δ 8.21 (d, J=7.6Hz, 1H), 7.60-7.56 (m, 2H), 7.56-7.48 (m, 2H), 2.61 (br d, J=6.7 Hz,2H), 1.18 (br t, J=7.2 Hz, 3H).

Step 3

A mixture of2-chloro-N-(6-chloro-4-ethylpyridazin-3-yl)benzenesulfonamide (54 mg,161.1 umol), tert-butyl((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(80 mg, 161.1 umol), K₃PO₄ (0.5 M, 644.6 uL) and[2-(2-aminophenyl)phenyl]-chloro-palladium;bis(1-adamantyl)-butyl-phosphane(11 mg, 16.1 umol) were degassed and purged with N₂ for 3 times andtaken up into a microwave tube in 2-methyltetrahydrofuran (2.5 mL). Thesealed tube was heated at 120° C. for 180 min under microwave. Thereaction was concentrated to give a residue. The residue was purified byprep-TLC (SiO₂) to give tert-butyl((1r,4r)-4-((6-(6-((2-chlorophenyl)sulfonamido)-4-ethylpyridazin-3-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(60 mg, crude). M+H⁺=666.3 (LCMS).

Step 4

To a solution of tert-butyl((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-4-ethylpyridazin-3-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(60 mg, 90.1 umol) in DCM (2.0 mL) was added TFA (1.0 mL). The mixturewas stirred at 20° C. for 0.5 h. The reaction was concentrated to give aresidue. The residue was dissolved in MeOH (1.0 mL) and basified pH to 7with NH₃.H₂O (25% solution). The residue was purified by prep-HPLC (FAcondition) to affordN-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-ethylpyridazin-3-yl)-2-chlorobenzenesulfonamide(5.1 mg, 7.9 umol, 8.8% yield, FA). M+H⁺=566.2 (LCMS); ¹H NMR (400 MHz,METHANOL-d₄) δ 9.08 (br s, 1H), 8.23 (br s, 1H), 8.03-7.38 (m, 7H), 3.99(br s, 1H), 3.23-3.01 (m, 3H), 2.67 (br s, 2H), 2.31 (br d, J=10.1 Hz,2H), 2.14 (br d, J=11.0 Hz, 2H), 1.66-1.44 (m, 4H), 1.33 (br t, J=7.4Hz, 3H), 1.10 (br t, J=7.1 Hz, 3H).

Example 6: Synthesis ofN-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-ethylpyridazin-3-yl)-2-chlorobenzenesulfonamide(100)

The title compound was synthesized according to the synthetic procedurereported for the preparation of compoundN-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-ethylpyridazin-3-yl)-2-chlorobenzenesulfonamide.(13.7 mg, 22.4 umol, 21.3% yield, FA). M+H⁺=566.2 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 9.06 (s, 1H), 8.57 (br s, 1H), 8.29-8.19 (m, 2H),8.16 (d, J=2.0 Hz, 1H), 8.05 (s, 1H), 7.59-7.46 (m, 3H), 4.05-3.94 (m,1H), 3.24-3.14 (m, 1H), 3.09 (q, J=7.5 Hz, 2H), 2.71 (q, J=7.4 Hz, 2H),2.32 (br d, J=11.4 Hz, 2H), 2.16 (br d, J=11.1 Hz, 2H), 1.69-1.44 (m,4H), 1.36 (t, J=7.5 Hz, 3H), 1.26 (t, J=7.5 Hz, 3H).

Example 7: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyrazin-2-yl)-2-chlorobenzenesulfonamide(98)

Step 1

To a solution of 6-methoxypyrazin-2-amine (100 mg, 799.2 umol) in CHCl₃(5.0 mL) was added NCS (107 mg, 799.2 umol). The mixture was stirred at40° C. for 12 h. The reaction was concentrated to give a residue. Theresidue was purified by prep-TLC (SiO₂) to give5-chloro-6-methoxypyrazin-2-amine (25 mg, 141.0 umol, 17.6% yield). ¹HNMR (400 MHz, CHLOROFORM-d) δ 7.33 (s, 1H), 4.42 (br s, 2H), 3.96 (s,3H).

Step 2

To a solution of 5-chloro-6-methoxypyrazin-2-amine (25 mg, 156.7 umol)in DCM (2.0 mL) was added pyridine (37 mg, 470.0 umol, 37.9 uL) and2-chlorobenzenesulfonyl chloride (50 mg, 235.0 umol, 32.0 uL). Themixture was stirred at 45° C. for 12 h. The reaction was concentrated togive a residue. The residue was purified by column chromatography (SiO₂)to afford 2-chloro-N-(5-chloro-6-methoxypyrazin-2-yl)benzenesulfonamide(110 mg). M+H⁺=333.8 (LCMS).

Step 3

A mixture of tert-butyl((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(80 mg, 161.1 umol),2-chloro-N-(5-chloro-6-methoxypyrazin-2-yl)benzenesulfonamide (54 mg,161.1 umol), K₃PO₄ (0.5 M, 644.6 uL),[2-(2-aminophenyl)phenyl]-chloro-palladium;bis(1-adamantyl)-butyl-phosphane(11 mg, 16.1 umol) in THF (2.0 mL) was degassed and purged with N₂ for 3times, and then the mixture was stirred at 80° C. for 12 h under N₂atmosphere. The reaction was concentrated to give a residue. The residuewas purified by prep-TLC (SiO₂) to give tert-butyl((1r,4r)-4-((6-(5-(2-chlorophenylsulfonamido)-3-methoxypyrazin-2-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(50 mg, 17.6 umol, 10.9% yield). M+H⁺=668.1 (LCMS).

Step 4

To a solution of tert-butyl((1r,4r)-4-((6-(5-(2-chlorophenylsulfonamido)-3-methoxypyrazin-2-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(50 mg, 74.8 umol) in DCM (2.0 mL) was added TFA (1.0 mL). The mixturewas stirred at 20° C. for 10 min. The reaction was concentrated to givea residue. The residue was dissolved in MeOH (1.0 mL) and basified pH to7 with NH₃.H₂O (25% solution). The residue was purified by prep-HPLC (FAcondition) to affordN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyrazin-2-yl)-2-chlorobenzenesulfonamide(6.4 mg, 10.1 umol, 13.6% yield, FA). M+H⁺=568.2 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 8.97 (s, 1H), 8.48 (br s, 1H), 8.33 (d, J=7.3 Hz,1H), 8.13 (br d, J=3.7 Hz, 2H), 7.87 (s, 1H), 7.64-7.44 (m, 3H), 3.96(br t, J=11.4 Hz, 1H), 3.74 (s, 3H), 3.23-3.10 (m, 1H), 3.04 (q, J=7.4Hz, 2H), 2.30 (br d, J=12.3 Hz, 2H), 2.13 (br d, J=11.2 Hz, 2H),1.65-1.41 (m, 4H), 1.31 (t, J=7.5 Hz, 3H).

Example 8: Synthesis of2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-hydroxycyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide(101)

Step 1

To a solution of 6-bromo-8-ethyl-2-iodoquinazoline (0.18 g, 495.8 umol)in n-BuOH (10.0 mL) was added 4-aminocyclohexanol (114 mg, 991.7 umol)and DIEA (192 mg, 1.4 mmol, 259.1 uL). The mixture was stirred at 100°C. for 12 h. The mixture was concentrated to get crude residue. Theresidue was purified by column chromatography (SiO₂) to afford(1r,4r)-4-((6-bromo-8-ethylquinazolin-2-yl)amino)cyclohexanol (160 mg,381.8 umol, 77.0% yield).

M+H⁺=352.1 (LCMS).

Step 2

To a solution of2-chloro-N-(6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)benzenesulfonamide(145 mg, 342.6 umol) and K₂CO₃ (71 mg, 513.9 umol) in dioxane (2.0 mL)and H₂O (0.2 mL) were added(1r,4r)-4-((6-bromo-8-ethylquinazolin-2-yl)amino)cyclohexanol (60 mg,171.3 umol) and Pd(dppf)Cl₂ (12 mg, 17.1 umol). The mixture was stirredat 90° C. for 12 h under N₂. The mixture was concentrated to get cruderesidue. The residue was purified by prep-TLC (SiO₂). The residue waspurified by prep-HPLC (FA condition) to afford2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-hydroxycyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide(24.0 mg, 38.7 umol, 22.6% yield, FA) as. M+H⁺=568.1 (LCMS); ¹H NMR(METHANOL-d₄, 400 MHz) 8.92 (s, 1H), 8.34-8.26 (m, 1H), 7.67-7.61 (m,3H), 7.61-7.55 (m, 2H), 7.54-7.48 (m, 1H), 6.64 (d, J=7.9 Hz, 1H),3.99-3.85 (m, 1H), 3.71-3.56 (m, 4H), 3.03 (q, J=7.5 Hz, 2H), 2.18 (brd, J=9.3 Hz, 2H), 2.02 (br d, J=9.8 Hz, 2H), 1.51-1.34 (m, 4H), 1.30 (t,J=7.5 Hz, 3H).

Example 9: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide(103)

Step 1

To a solution of 5-bromo-6-methoxypyridin-2-amine (50 mg, 246.2 umol)and 2-methylbenzene-1-sulfonyl chloride (70.4 mg, 369.3 umol, 53.3 uL)in DCM (3.0 mL) was added pyridine (58.4 mg, 738.7 umol, 59.6 uL), themixture was stirred at 45° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure to give a residue. The residue waspurified by prep-TLC (SiO₂) to giveN-(5-bromo-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide (80 mg,208.2 umol, 84.5% yield). M+H⁺=359.1 (LCMS).

Step 2

A mixture ofN-(5-bromo-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide (29 mg,83.9 umol), tert-butyl((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(50 mg, 100.7 umol), K₂CO₃ (34 mg, 251.7 umol), and Pd(dppf)Cl₂ (6 mg,8.3 umol) in dioxane (2.0 mL) and H₂O (0.2 mL) was degassed and purgedwith N₂ for 3 times, and then the mixture was stirred at 90° C. for 12 hunder N₂ atmosphere. The reaction mixture was concentrated under reducedpressure to give a residue.

The residue was purified by prep-TLC (SiO₂) to give tert-butyl((1r,4r)-4-((8-ethyl-6-(2-methoxy-6-(2-methylphenylsulfonamido)pyridin-3-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(30 mg, 36.5 umol, 43.4% yield). M+H⁺=647.4 (LCMS).

Step 3

To a solution of tert-butyl((1r,4r)-4-((8-ethyl-6-(2-methoxy-6-(2-methylphenylsulfonamido)pyridin-3-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(30 mg, 46.3 umol) in TFA (1.0 mL) and DCM (2.0 mL) was stirred at 20°C. for 0.5 h. The mixture was concentrated under reduced pressure togive a residue. The residue was dissolved in MeOH (2.0 mL) and basifiedpH to 8 with NH₃.H₂O (25% solution), concentrated to give a residue. Theresidue was purified by pre-HPLC (FA condition) to affordN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide(21.3 mg, 35.5 umol, 76.7% yield, FA). M+H⁺=547.3 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 8.94 (s, 1H), 8.54 (br s, 1H), 8.16 (d, J=7.5 Hz,1H), 7.69-7.59 (m, 3H), 7.53-7.46 (m, 1H), 7.41-7.32 (m, 2H), 6.64 (d,J=7.9 Hz, 1H), 4.02-3.90 (m, 1H), 3.71 (s, 3H), 3.22-3.11 (m, 1H), 3.03(q, J=7.5 Hz, 2H), 2.70 (s, 3H), 2.30 (br d, J=11.0 Hz, 2H), 2.14 (br d,J=11.7 Hz, 2H), 1.67-1.40 (m, 4H), 1.30 (t, J=7.5 Hz, 3H).

Example 10: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-2-methylbenzenesulfonamide(112)

The title compound was synthesized according to the synthetic procedurereported for the preparation ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide(18.1 mg, 22.0% yield, FA). M+H⁺=531.2 (LCMS); ¹H NMR (400 MHz,METHANOL-d₄) δ 8.99 (s, 1H), 8.55 (br s, 1H), 8.09 (d, J=7.5 Hz, 1H),7.62 (d, J=8.8 Hz, 1H), 7.52-7.39 (m, 3H), 7.37-7.30 (m, 2H), 7.15 (d,J=8.8 Hz, 1H), 4.04-3.92 (m, 1H), 3.22-3.12 (m, 1H), 3.06 (q, J=7.4 Hz,2H), 2.72 (s, 3H), 2.43-2.26 (m, 5H), 2.14 (br d, J=11.9 Hz, 2H),1.68-1.42 (m, 4H), 1.32 (t, J=7.5 Hz, 3H).

Example 11: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-cyanobenzenesulfonamide(102)

The title compound was synthesized according to the synthetic procedurereported for the preparation ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide(5.6 mg, 9.4 umol, 15.1% yield, FA). M+H⁺=544.3 (LCMS); ¹H NMR (400 MHz,METHANOL-d₄) δ 8.92 (s, 1H), 8.51 (br s, 1H), 8.34 (d, J=7.7 Hz, 1H),7.97 (d, J=7.7 Hz, 1H), 7.91-7.73 (m, 2H), 7.49-7.33 (m, 3H), 6.67 (d,J=7.9 Hz, 1H), 4.00-3.89 (m, 1H), 3.50 (s, 3H), 3.21-3.09 (m, 1H),2.28-2.07 (m, 7H), 1.68-1.39 (m, 4H).

Example 12: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-(trifluoromethoxy)pyridin-2-yl)-2-chlorobenzenesulfonamide(107)

Step 1

To a solution of LDA (2 M, 2.5 mL) in THF (27.0 mL) was added dropwise asolution of 2-chloro-6-(trifluoromethoxy)pyridine (900 mg, 4.6 mmol) inTHF (9.0 mL) at −78° C. under N₂. The mixture was stirred at −78° C. for2 h. A solution of I₂ (1.3 g, 5.0 mmol, 1.0 mL) in THF (9.0 mL) wasadded at −78° C. Then the mixture was slowly warmed to 25° C. andstirred for 12 h. The reaction was quenched with saturated NH₄Cl (15.0mL) and extracted with ethyl acetate (15.0 mL×3). The combined organicphase was washed with brine (15 mL×3), dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue. The residue was purified byprep-TLC (SiO₂) to give 6-chloro-3-iodo-2-(trifluoromethoxy)pyridine(1.2 g, 3.0 mmol, 65.2% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.10(d, J=8.1 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H).

Step 2

A mixture of 6-chloro-3-iodo-2-(trifluoromethoxy)pyridine (63 mg, 193.4umol), tert-butyl((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(80 mg, 161.1 umol), K₂CO₃ (34 mg, 241.7 umol) and Pd(dppf)Cl₂ (12 mg,16.1 umol) in dioxane (2.0 mL) and H₂O (0.2 mL) was degassed and purgedwith N₂ for 3 times, and then the mixture was stirred at 80° C. for 12 hunder N₂ atmosphere. The reaction was concentrated to give a residue.The residue was purified by prep-TLC (SiO₂) to afford tert-butyl((1r,4r)-4-((6-(6-chloro-2-(trifluoromethoxy)pyridin-3-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(90 mg, 96.8 umol, 60.1% yield). M+H⁺=566.1 (LCMS).

Step 3

A mixture of tert-butyl((1r,4r)-4-((6-(6-chloro-2-(trifluoromethoxy)pyridin-3-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(90 mg, 159.0 umol), 2-chlorobenzenesulfonamide (34 mg, 174.9 umol),Cs₂CO₃ (155 mg, 477.0 umol),dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (8 mg, 15.9umol) and[2-(2-aminoethyl)phenyl]-chloro-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (11 mg, 15.9 umol) in THF (5.0 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 80° C.for 12 h under N₂ atmosphere. The reaction was concentrated to give aresidue. The residue was purified by prep-TLC (SiO₂) to give tert-butyl((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-2-(trifluoromethoxy)pyridin-3-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(80 mg, 33.3 umol, 20.9% yield). M+H⁺=721.3 (LCMS).

Step 4

To a solution of tert-butyl((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-2-(trifluoromethoxy)pyridin-3-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(80 mg, 110.9 umol) in DCM (2.0 mL) was added TFA (1.0 mL). The mixturewas stirred at 20° C. for 15 min. The reaction was concentrated to givea residue. The residue was dissolved in MeOH (2.0 mL) and basified pH to7 with NH₃.H₂O (25% solution). The residue was purified by prep-HPLC (FAcondition) to affordN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-(trifluoromethoxy)pyridin-2-yl)-2-chlorobenzenesulfonamide(14 mg, 20.6 umol, 18.6% yield, FA). M+H⁺=621.2 (LCMS); ¹H NMR (400 MHz,METHANOL-d₄) δ 8.99 (s, 1H), 8.50 (br s, 1H), 8.33-8.24 (m, 1H), 7.88(d, J=8.2 Hz, 1H), 7.64-7.47 (m, 5H), 7.04 (d, J=8.2 Hz, 1H), 3.99 (tt,J=3.9, 11.2 Hz, 1H), 3.19 (tt, J=3.9, 11.5 Hz, 1H), 3.06 (q, J=7.5 Hz,2H), 2.32 (br d, J=11.6 Hz, 2H), 2.16 (br d, J=11.9 Hz, 2H), 1.68-1.42(m, 4H), 1.32 (t, J=7.5 Hz, 3H).

Example 13: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methoxybenzenesulfonamide(109)

Step 1

To a solution of 5-bromo-6-chloro-pyridin-2-amine (500 mg, 2.41 mmol) inTHF (8.0 mL) was added NaH (144 mg, 3.6 mmol, 60%) stirred for 30 min,then 2-methoxybenzenesulfonyl chloride (498 mg, 2.4 mmol) in THF (2.0mL) was added. The mixture was stirred at 25° C. for 2 h. The reactionmixture was quenched by addition saturated ammonium chloride solution(10.0 mL), and then added H2O (10.0 mL) and extracted with ethyl acetate(30.0 mL×3). The combined organic layers were washed with brine (30.0mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The residue was purified by column chromatography(SiO₂) to affordN-(5-bromo-6-chloropyridin-2-yl)-2-methoxybenzenesulfonamide (200 mg,490.4 umol, 20.3% yield). M+H⁺=379.0 (LCMS).

Step 2

A solution ofN-(5-bromo-6-chloropyridin-2-yl)-2-methoxybenzenesulfonamide (200 mg,529.6 umol) in NaOMe (5 mL, 30% solution) was stirred at 70° C. for 3 h.The reaction mixture was added H₂O (30.0 mL) and extracted with ethylacetate (20.0 mL×3). The combined organic phase was washed with brine(10.0 mL×3), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum to give a residue. The residue was purified by prep-TLC (SiO₂) toafford N-(5-bromo-6-methoxypyridin-2-yl)-2-methoxybenzenesulfonamide(100 mg, 219.7 umol, 41.4% yield). M+H⁺=372.9 (LCMS).

Step 3

A mixture ofN-(5-bromo-6-methoxypyridin-2-yl)-2-methoxybenzenesulfonamide (100 mg,267.9 umol), tert-butyl((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(159 mg, 321.5 umol), K₂CO₃ (111 mg, 803.8 umol), Pd(dppf)Cl₂ (19 mg,26.79 umol) in dioxane (2.0 mL) and H₂O (0.2 mL) was degassed and purgedwith N₂ for 3 times, and then the mixture was stirred at 90° C. for 12 hunder N₂ atmosphere. The reaction mixture was concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂) to affordtert-butyl ((1r,4r)-4-((8-ethyl-6-(2-methoxy-6-(2-methoxyphenylsulfonamido)pyridin-3-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate (160mg, 91.4 umol, 34.1% yield). M+H⁺=663.4 (LCMS).

Step 4

To a solution of tert-butyl((1r,4r)-4-((8-ethyl-6-(2-methoxy-6-(2-methoxyphenylsulfonamido)pyridin-3-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate (160mg, 241.4 umol) in DCM (2.0 mL) was added TFA (1.5 g, 13.5 mmol, 1 mL).The mixture was stirred at 25° C. for 0.5 h. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted with MeOH,(2.0 mL), then used the ammonium hydroxide (25% solution) to adjust thepH to 7-8, then filtered. The mixture was purified by prep-HPLC (FAcondition) to affordN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methoxybenzenesulfonamide(14.7 mg, 23.9 umol, 9.9% yield, FA). M+H⁺=563.2 (LCMS); ¹H NMR(METHANOL-d₄, 400 MHz) δ 8.96 (s, 1H), 8.57 (br s, 1H), 8.04 (dd, J=1.5,7.8 Hz, 1H), 7.76-7.54 (m, 4H), 7.28-7.01 (m, 2H), 6.72 (d, J=7.9 Hz,1H), 3.96 (s, 4H), 3.76 (s, 3H), 3.18 (br t, J=11.3 Hz, 1H), 3.04 (q,J=7.5 Hz, 2H), 2.32 (br d, J=11.5 Hz, 2H), 2.16 (br d, J=10.9 Hz, 2H),1.69-1.41 (m, 4H), 1.32 (t, J=7.5 Hz, 3H).

Example 14: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-3-methylbenzenesulfonamide(113)

The title compound was synthesized according to the synthetic procedurereported for the preparation ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methoxybenzenesulfonamide.16.4 mg, 22.3% yield. M+H⁺=531.3 (LCMS); ¹HNMR (DMSO-d₆, 400 MHz) δ 9.02(br s, 1H), 7.70-7.60 (m, 2H), 7.47 (br d, J=8.6 Hz, 2H), 7.39-7.27 (m,4H), 6.80 (br d, J=8.6 Hz, 1H), 6.62 (br d, J=6.6 Hz, 1H), 6.06 (br s,1H), 3.77 (s, 1H), 3.23 (s, 1H), 2.95 (q, J=7.4 Hz, 2H), 2.34 (s, 3H),2.29-2.21 (m, 3H), 2.03 (brs, 2H), 1.85 (br s, 2H), 1.41-1.28 (m, 4H),1.24 (br t, J=7.4 Hz, 3H).

Example 15: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(110)

Step 1

To a solution of 1-(2-bromo-5-fluoro-phenyl)ethanone (9.2 g, 42.3 mmol)in MeOH (92.0 mL) was cooled to 0° C. and added NaBH₄ (2.2 g, 59.3mmol). The mixture was stirred at 25° C. for 1 h. The reaction mixturewas concentrated under reduced pressure to give a residue. The residuewas diluted with saturated NaHCO₃ solution (100.0 mL) and the mixturewas extracted with ethyl acetate (100.0 mL×3). The combined organiclayers were washed with brine (50.0 mL×3), dried over Na₂SO₄, filteredand concentrated to afford 1-(2-bromo-5-fluorophenyl)ethanol (9 g,crude).

Step 2

To a solution of 1-(2-bromo-5-fluorophenyl)ethanol (9 g, 41.0 mmol) andEt₃SiH (9.5 g, 82.1 mmol, 13.1 mL) in DCM (100.0 mL) was added BF₃.Et₂O(11.6 g, 82.1 mmol, 10.1 mL) at 0° C. The mixture was stirred at 35° C.for 36 h. The mixture was quenched by addition Sat.NaHCO₃ (100.0 mL) at0° C., extracted with DCM (100.0 mL×3). The combined organic layers werewashed with brine (50.0 mL×3), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂) to afford1-bromo-2-ethyl-4-fluorobenzene (6.3 g, 24.8 mmol, crude). ¹H NMR(CHLOROFORM-d, 400 MHz): δ 7.53-7.43 (m, 1H), 6.97 (dd, J=2.9, 9.5 Hz,1H), 6.79 (dt, J=3.0, 8.3 Hz, 1H), 2.74 (q, J=7.5 Hz, 2H), 1.34-1.16 (m,6H).

Step 3

To a solution of 1-bromo-2-ethyl-4-fluorobenzene (2.0 g, 9.8 mmol) inTHF (35.0 mL) was added LDA (2 M, 5.9 mL) at −78° C. The mixture wasstirred at −78° C. for 1 h. And then DMF (935 mg, 12.8 mmol, 985.1 uL)was added at −78° C. for 1 h. The reaction mixture was diluted withNH₄Cl (30.0 mL) and extracted with ethyl acetate (10.0 mL×3). Thecombined organic layers were washed with brine (10.0 mL×3), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂) toafford 5-bromo-4-ethyl-2-fluorobenzaldehyde (1.0 g, 3.4 mmol, 35.1%yield). ¹H NMR (CHLOROFORM-d, 400 MHz): δ 10.25 (s, 1H), 8.02 (d, J=7.0Hz, 1H), 7.08 (d, J=11.0 Hz, 1H), 2.80 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5Hz, 3H).

Step 4

To a solution of guanidine (262 mg, 2.1 mmol, H₂CO₃) and DIEA (839 mg,6.4 mmol, 1.1 mL) in DMA (10.0 mL) was added a solution of5-bromo-4-ethyl-2-fluorobenzaldehyde (0.5 g, 2.1 mmol) in DMA (1.5 mL).Then the mixture was stirred at 160° C. for 2 h. The mixture wasconcentrated to get crude residue and then H₂O (30.0 mL) was added. Itwas extracted with ethyl acetate (30.0 mL×3). The combined organiclayers were washed with brine (20.0 mL×3), dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a residue. The residuewas purified by column chromatography (SiO₂) to afford6-bromo-7-ethylquinazolin-2-amine (130 mg, 217.2 umol, 10.0% yield).M+H⁺=251.9 (LCMS).

Step 5

To a solution of 6-bromo-7-ethylquinazolin-2-amine (130 mg, 515.6 umol)and diiodomethane (690 mg, 2.5 mmol, 207.9 uL) in THF (2.0 mL) was addedCuI (98 mg, 515.6 umol) isopentyl nitrite (181 mg, 1.5 mmol, 208.3 uL).The mixture was stirred at 65° C. for 12 h. The mixture was poured intoNH₃.H₂O (2.0 mL, 25%) and filtered. The filtrate was extracted withethyl acetate (5.0 mL×3). The combined organic layers were washed withbrine (5.0 mL×3), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by prep-TLC(SiO₂) to afford 6-bromo-7-ethyl-2-iodoquinazoline (50 mg, 110.0 umol,21.3% yield). M+H⁺=362.8 (LCMS); Step 6:

To a solution of 6-bromo-7-ethyl-2-iodoquinazoline (50 mg, 137.7 umol)and DIEA (53 mg, 413.2 umol, 71.9 uL) in n-BuOH (2.0 mL) was addedtert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (59 mg, 275.4 umol). Themixture was stirred at 120° C. for 12 h. The mixture was concentrated toget crude residue. The residue was purified by prep-TLC (SiO₂) to affordtert-butyl((1r,4r)-4-((6-bromo-7-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(50 mg, crude).

Step 7

To a solution of tert-butyl((1r,4r)-4-((6-bromo-7-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(50 mg, 111.2 umol) and K₂CO₃ (15 mg, 111.2 umol) in dioxane (2.0 mL)and H₂O (0.2 mL) were added2-chloro-N-(6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)benzenesulfonamide(56 mg, 133.5 umol) and Pd(dppf)Cl₂ (81 mg, 111.2 umol). The mixture wasstirred at 90° C. for 12 h under N₂. The mixture was concentrated to getcrude residue. The residue was purified by prep-TLC (SiO₂) to affordtert-butyl((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-2-methoxypyridin-3-yl)-7-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(40 mg, crude).

Step 8

A solution of tert-butyl((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-2-methoxypyridin-3-yl)-7-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate(40 mg, 59.9 umol) in TFA (1.0 mL) and DCM (2.0 mL) was stirred at 25°C. for 10 min. The mixture was concentrated to get crude residue. Theresidue was dissolved in MeOH (2.0 mL) and basified pH to 8 with NH₃.H₂O(25% solution), concentrated to give a residue. The residue was purifiedby prep-HPLC (FA condition) to affordN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(14.0 mg, 22.1 umol, 36.9% yield, FA). M+H⁺=567.2 (LCMS); ¹H NMR(METHANOL-d₄, 400 MHz) δ 8.91 (s, 1H), 8.52 (br s, 1H), 8.33-8.27 (m,1H), 7.61-7.56 (m, 2H), 7.53-7.46 (m, 1H), 7.44-7.37 (m, 3H), 6.62 (d,J=7.7 Hz, 1H), 4.02-3.87 (m, 1H), 3.55 (s, 3H), 3.22-3.11 (m, 1H), 2.46(br d, J=7.1 Hz, 2H), 2.23 (br d, J=11.5 Hz, 2H), 2.17-2.05 (m, 2H),1.67-1.55 (m, 2H), 1.52-1.41 (m, 2H), 1.06 (t, J=7.6 Hz, 3H).

Example 16: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-methylquinazolin-6-yl)-6-methylpyridin-2-yl)-2-chlorobenzenesulfonamide(106)

The title compound was synthesized according to the synthetic procedurereported for the preparation ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(5.5 mg, 9.1 umol, 14.6% yield, FA). M+H⁺=537.3 (LCMS); ¹H NMR (400 MHz,METHANOL-d₄) δ 8.95 (s, 1H), 8.47 (br s, 1H), 8.26-8.19 (m, 1H),7.58-7.42 (m, 6H), 7.18 (d, J=8.8 Hz, 1H), 4.02-3.88 (m, 1H), 3.14 (dt,J=4.0, 7.7 Hz, 1H), 2.28-2.05 (m, 10H), 1.72-1.53 (m, 2H), 1.52-1.39 (m,2H).

Example 17:N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(104)

The title compound was synthesized according to the synthetic procedurereported for the preparation ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(11.6 mg, 19.1 umol, 24.9% yield, FA). M+H⁺=553.1 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 8.90 (s, 1H), 8.56 (br s, 1H), 8.29 (d, J=7.7 Hz,1H), 7.62-7.53 (m, 2H), 7.52-7.44 (m, 1H), 7.38 (dd, J=7.3, 15.0 Hz,3H), 6.59 (d, J=7.7 Hz, 1H), 3.93 (tt, J=3.8, 11.3 Hz, 1H), 3.54 (s,3H), 3.12 (tt, J=3.9, 11.7 Hz, 1H), 2.30-2.00 (m, 7H), 1.66-1.52 (m,2H), 1.52-1.39 (m, 2H).

Example 18:N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-methylquinazolin-6-yl)-6-ethylpyridin-2-yl)-2-chlorobenzenesulfonamide(105)

The title compound was synthesized according to the synthetic procedurereported for the preparation ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzennesulfonamide.(16.2 mg, 26.9 umol, 17.6% yield, FA). M+H⁺=551.1 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 8.94 (s, 1H), 8.47 (br s, 1H), 8.24 (d, J=7.5 Hz,1H), 7.61-7.38 (m, 6H), 7.09 (d, J=8.8 Hz, 1H), 3.95 (tdd, J=3.5, 7.5,15.0 Hz, 1H), 3.21-3.10 (m, 1H), 2.53-2.40 (m, 1H), 2.33 (qd, J=7.4,14.3 Hz, 1H), 2.26-2.06 (m, 7H), 1.68-1.54 (m, 2H), 1.53-1.38 (m, 2H),0.98 (t, J=7.6 Hz, 3H).

Example 19: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-5-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(114)

The title compound was synthesized according to the synthetic procedurereported for the preparation ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(5.7 mg, 9.3 umol, 20.3% yield, FA). M+H⁺=553.3 (LCMS); ¹H NMR (400 MHz,METHANOL-d₄) δ 9.29 (s, 1H), 8.55 (br s, 1H), 8.33 (d, J=7.3 Hz, 1H),7.67-7.57 (m, 2H), 7.57-7.48 (m, 1H), 7.46-7.34 (m, 3H), 6.65 (d, J=7.8Hz, 1H), 3.97 (br t, J=11.3 Hz, 1H), 3.59 (s, 3H), 3.17 (ddd, J=4.3,7.6, 11.5 Hz, 1H), 2.35 (s, 3H), 2.25 (br d, J=11.5 Hz, 2H), 2.14 (br d,J=11.5 Hz, 2H), 1.69-1.56 (m, 2H), 1.55-1.42 (m, 2H).

Example 20: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide(111)

Step 1

To a solution of 5-bromo-6-methylpyridin-2-amine (0.5 g, 2.6 mmol) inDCM (30.0 mL) was added pyridine (634 mg, 8.0 mmol, 647.3 uL) andbenzenesulfonyl chloride (519 mg, 2.9 mmol, 376.4 uL). The mixture wasstirred at 45° C. for 12 h. The reaction was concentrated to give aresidue. The residue was purified by flash silica gel chromatography(SiO₂) to afford N-(5-bromo-6-methylpyridin-2-yl)benzenesulfonamide (780mg, 1.8 mmol, 68.3% yield). M+H⁺=329.0 (LCMS).

Step 2

A mixture of tert-butyl((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(60 mg, 120.8 umol), N-(5-bromo-6-methylpyridin-2-yl)benzenesulfonamide(44 mg, 132.9 umol), K₂CO₃ (25 mg, 181.3 umol) and Pd(dppf)Cl₂ (9 mg,12.1 umol) in dioxane (2.0 mL) and H₂O (0.2 mL) was degassed and purgedwith N₂ for 3 times, and then the mixture was stirred at 90° C. for 12 hunder N₂ atmosphere. The reaction was concentrated to give a residue.The residue was purified by prep-TLC (SiO₂) to afford tert-butyl((1r,4r)-4-((8-ethyl-6-(2-methyl-6-(phenylsulfonamido)pyridin-3-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(60 mg, 55.9 umol, 46.3% yield). M+H⁺=617.4 (LCMS).

Step 3

To a solution of tert-butyl((1r,4r)-4-((8-ethyl-6-(2-methyl-6-(phenylsulfonamido)pyridin-3-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate(60 mg, 55.9 umol) in DCM (2.0 mL) was added TFA (1.0 mL). The mixturewas stirred at 20° C. for 0.5 h. The reaction was concentrated to give aresidue. The residue was dissolved in MeOH (2.0 mL) and basified pH to 7with NH₃.H₂O (25% solution). The residue was purified by prep-HPLC (FAcondition) to affordN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide(13.4 mg, 24.0 umol, 42.8% yield, FA). M+H⁺=517.2 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 9.00 (s, 1H), 8.58 (br s, 1H), 7.99 (br d, J=7.1 Hz,2H), 7.64 (d, J=8.8 Hz, 1H), 7.60-7.45 (m, 5H), 7.22 (br d, J=8.7 Hz,1H), 4.05-3.93 (m, 1H), 3.22-3.02 (m, 3H), 2.39 (s, 3H), 2.32 (br d,J=11.6 Hz, 2H), 2.15 (br d, J=12.0 Hz, 2H), 1.69-1.43 (m, 4H), 1.39-1.28(m, 3H).

Example 21: Synthesis of2-chloro-N-(4-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluoro-5-methoxyphenyl)benzenesulfonamide(120)

Step 1

To a solution of 2-bromo-4-fluoro-5-nitrophenol (1.0 g, 4.2 mmol) in DMF(25.0 mL) was added K₂CO₃ (1.2 g, 8.9 mmol), and then iodomethane (1.2g, 8.4 mmol, 527.5 uL) at 0° C. was added dropwise and after completeaddition, the reaction mixture was warmed to 45° C. and stirred for 12h. The mixture (contain other batch 1 g) was diluted with H₂O (100 mL)and extracted with ethyl acetate (30.0 mL×3) and washed with brine (30.0mL×3). The organic layer was dried over anhydrous Na₂SO₄, then filteredand concentrated to afford a crude1-bromo-5-fluoro-2-methoxy-4-nitrobenzene (2.0 g). ¹H NMR (400 MHz,CHLOROFORM-d) (7.61-7.54 (m, 2H), 3.99 (s, 3H).

Step 2

To a solution of 1-bromo-5-fluoro-2-methoxy-4-nitrobenzene (2.0 g, 8.0mmol) in EtOH (45.0 mL) and H₂O (9.0 mL) was added Fe (2.2 g, 40.0 mmol)and NH₄Cl (1.2 g, 24.0 mmol, 839.0 uL). The mixture was stirred at 80°C. for 12 h. The reaction mixture was filtered, the filter liquor wasconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂) to afford 4-bromo-2-fluoro-5-methoxyaniline (1.2g, 4.4 mmol, 55.1% yield). M+H⁺=221.9 (LCMS); ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.10 (d, J=10.0 Hz, 1H), 6.29 (d, J=7.8 Hz, 1H), 3.75(s, 3H).

Step 3

To a solution of 4-bromo-2-fluoro-5-methoxyaniline (500 mg, 2.2 mmol) inpyridine (10.0 mL) was added 2-chlorobenzenesulfonyl chloride (575 mg,2.7 mmol, 371.3 uL). The mixture was stirred at 45° C. for 12 h. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by column chromatography (SiO₂) to affordN-(4-bromo-2-fluoro-5-methoxyphenyl)-2-chlorobenzenesulfonamide (890 mg,1.5 mmol, 69.4% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.95 (d, J=7.6Hz, 1H), 7.52-7.40 (m, 2H), 7.34-7.25 (m, 1H), 7.13 (d, J=9.3 Hz, 1H),7.06 (d, J=7.0 Hz, 1H), 3.76 (s, 3H).

Step 4

A mixture ofN-(4-bromo-2-fluoro-5-methoxyphenyl)-2-chlorobenzenesulfonamide (783 mg,1.9 mmol),8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline(500 mg, 1.6 mmol), K₂CO₃ (686 mg, 4.9 mmol), Pd(dppf)Cl₂ (121 mg, 165umol) in dioxane (20.0 mL) and H₂O (2.0 mL) was degassed and purged withN₂ for 3 times, and then the mixture was stirred at 90° C. for 12 hunder N₂ atmosphere. The reaction mixture was concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂) toafford2-chloro-N-(4-(8-ethyl-2-fluoroquinazolin-6-yl)-2-fluoro-5-methoxyphenyl)benzenesulfonamide (760 mg, 1.0 mmol, 63.7% yield). M+H⁺=490.2 (LCMS).

Step 5

To a solution of2-chloro-N-(4-(8-ethyl-2-fluoroquinazolin-6-yl)-2-fluoro-5-methoxyphenyl)benzenesulfonamide (200 mg, 408.2 umol) in n-BuOH (5.0 mL) was addedDIEA (422 mg, 3.2 mmol, 568.8 uL) and(1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (291 mg, 1.6 mmol, HCl).The mixture was stirred at 100° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (FA condition) to afford2-chloro-N-(4-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluoro-5-methoxyphenyl)benzenesulfonamide(60.4 mg, 91.4 umol, 22.3% yield, FA). M+H⁺=612.2 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 8.98 (s, 1H), 8.53 (br s, 1H), 8.09 (dd, J=1.3, 7.9Hz, 1H), 7.69-7.58 (m, 4H), 7.47 (ddd, J=1.8, 6.7, 8.1 Hz, 1H), 7.10(dd, J=2.0, 8.8 Hz, 2H), 3.99 (tt, J=4.0, 11.6 Hz, 1H), 3.73 (s, 3H),3.28-3.20 (m, 1H), 3.06 (q, J=7.5 Hz, 2H), 2.88 (s, 6H), 2.47-2.35 (m,2H), 2.26-2.14 (m, 2H), 1.82-1.67 (m, 2H), 1.57-1.43 (m, 2H), 1.33 (t,J=7.5 Hz, 3H).

Example 22: Synthesis of2-chloro-N-(4-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-2-fluoro-5-methoxyphenyl)benzenesulfonamide(121)

Step 1

To a solution of2-chloro-N-(4-(8-ethyl-2-fluoroquinazolin-6-yl)-2-fluoro-5-methoxyphenyl)benzenesulfonamide(200 mg, 408.2 umol) in n-BuOH (5.0 mL) was added DIEA (158 mg, 1.2mmol, 213.3 uL) and tert-butyl((1r,4r)-4-aminocyclohexyl)(methyl)carbamate (279 mg, 1.2 mmol). Themixture was stirred at 100° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂) to afford tert-butyl((1r,4r)-4-((6-(4-(2-chlorophenylsulfonamido)-5-fluoro-2-methoxyphenyl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)(methyl)carbamate(175 mg, 238.1 umol, 58.3% yield). M+H⁺=698.4 (LCMS).

Step 2

To a solution of tert-butyl((1r,4r)-4-((6-(4-(2-chlorophenylsulfonamido)-5-fluoro-2-methoxyphenyl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)(methyl)carbamate(175 mg, 250.6 umol) in DCM (2.0 mL) was added TFA (1.5 g, 13.5 mmol,1.0 mL). The mixture was stirred at 25° C. for 0.5 h. The reactionmixture was concentrated under reduced pressure. And then the mixture inMeOH (2.0 mL) was adjusted to pH=7 by adding NH₃. H₂O (25% solution).The residue was purified by prep-HPLC (FA condition) to give2-chloro-N-(4-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-2-fluoro-5-methoxyphenyl)benzenesulfonamide(101.7 mg, 157.8 umol, 62.9% yield, FA). M+H⁺=598.2 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 8.98 (s, 1H), 8.31 (s, 1H), 8.09 (d, J=8.1 Hz, 1H),7.71-7.56 (m, 4H), 7.51-7.42 (m, 1H), 7.16-7.06 (m, 2H), 4.07-3.93 (m,1H), 3.73 (s, 3H), 3.16-2.99 (m, 3H), 2.75 (s, 3H), 2.36 (br d, J=11.6Hz, 2H), 2.26 (br d, J=11.7 Hz, 2H), 1.68-1.41 (m, 4H), 1.32 (t, J=7.5Hz, 3H).

Example 23: SynthesisN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-(methoxymethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(129)

Step 1

To a solution of 6-bromo-2-fluoro-8-methylquinazoline (0.5 g, 2.2 mmol)in ACN (10.0 mL) was added AIBN (37 mg, 228.1 umol) and NBS (487 mg, 2.7mmol). The mixture was stirred at 90° C. for 12 h. The reaction mixturewas concentrated under reduced pressure. The residue was purified bycolumn chromatography (SiO₂) to afford6-bromo-8-(bromomethyl)-2-fluoroquinazoline (0.7 g, 1.7 mmol, 78.6%yield). M+H⁺=320.9 (LCMS). Step 2:

To a solution of 6-bromo-8-(bromomethyl)-2-fluoroquinazoline (150 mg,468.8 umol) in n-BuOH (4.0 mL) was added DIEA (181 mg, 1.4 mmol, 244.9uL), and tert-butyl N-(4-aminocyclohexyl)carbamate (100 mg, 468.8umol,). The mixture was stirred at 25° C. for 12 h. The reaction mixturewas concentrated under reduced pressure to afford tert-butyl((1r,4r)-4-((6-bromo-8-(bromomethyl)quinazolin-2-yl)amino)cyclohexyl)carbamate(240 mg, crude).

Step 3

To a solution of tert-butyl((1r,4r)-4-((6-bromo-8-(bromomethyl)quinazolin-2-yl)amino)cyclohexyl)carbamate(200 mg, 388.9 umol) in MeOH (2.0 mL) was added NaOMe (2.0 mL, 30%solution). The mixture was stirred at 25° C. for 2 h. The reactionmixture was concentrated under reduced pressure. The residue waspurified by column chromatography (SiO₂) to afford tert-butyl((1r,4r)-4-((6-bromo-8-(methoxymethyl)quinazolin-2-yl)amino)cyclohexyl)carbamate(60 mg, 51.5 umol, 13.2% yield). M+H⁺=465.3 (LCMS).

Step 4

A mixture of tert-butyl((1r,4r)-4-((6-bromo-8-(methoxymethyl)quinazolin-2-yl)amino)cyclohexyl)carbamate(60 mg, 128.9 umol),2-chloro-N-(6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)benzenesulfonamide(54 mg, 128.9 umol), K₂CO₃ (53 mg, 386.7 umol), Pd(dppf)Cl₂ (9 mg, 12.8umol) in dioxane (2.0 mL) and H₂O (0.2 mL) was degassed and purged withN₂ for 3 times, and then the mixture was stirred at 90° C. for 12 hunder N₂ atmosphere. The reaction mixture was concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂) to affordtert-butyl((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-2-methoxypyridin-3-yl)-8-(methoxymethyl)quinazolin-2-yl)amino)cyclohexyl)carbamate(50 mg, 50.5 umol, 39.1% yield). M+H⁺=683.1 (LCMS).

Step 5

To a solution of tert-butyl((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-2-methoxypyridin-3-yl)-8-(methoxymethyl)quinazolin-2-yl)amino)cyclohexyl)carbamate(50 mg, 73.1 umol) in DCM (2.0 mL) was added TFA (1.0 mL). The mixturewas stirred at 25° C. for 0.5 h. The reaction mixture was concentratedunder reduced pressure. The residue was added dichloromethane (2.0 mL)and NH₃.H₂O (25% solution) to pH 7, concentrated under reduced pressureagain. The residue was purified by prep-HPLC (FA condition) to affordN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-(methoxymethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(12.4 mg, 18.5 umol, 25.2% yield, FA). M+H⁺=583.2 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 9.00 (s, 1H), 8.56 (br s, 1H), 8.33 (br d, J=7.7 Hz,1H), 7.88 (br s, 1H), 7.78 (br s, 1H), 7.67 (br d, J=7.5 Hz, 1H), 7.59(br s, 2H), 7.54 (br d, J=7.1 Hz, 1H), 6.65 (br d, J=7.8 Hz, 1H), 3.97(br s, 1H), 3.67 (s, 3H), 3.49 (s, 3H), 3.17 (br s, 1H), 2.31 (br d,J=10.5 Hz, 2H), 2.15 (br d, J=10.8 Hz, 2H), 1.73-1.41 (m, 4H).

Example 24: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-(1,1-difluoroethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(123)

Step 1

The solution of 1-(5-bromo-2-fluoro-phenyl)ethanone (1.0 g, 4.6 mmol) inDAST (12.2 g, 75.6 mmol, 10.0 mL) was stirred at 45° C. for 12 h. Themixture was poured into ice Sat. NaHCO₃ (100.0 mL) and extracted withethyl acetate (10.0 mL×3). The combined organic layers were washed withbrine (10.0 mL×3), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=I/O to 100/1) toafford 4-bromo-2-(1,1-difluoroethyl)-1-fluorobenzene (1.0 g, 4.1 mmol,90.8% yield). ¹H NMR (CHLOROFORM-d, 400 MHz): δ 7.68 (dd, J=2.4, 6.6 Hz,1H), 7.57-7.50 (m, 1H), 7.07-6.98 (m, 1H), 1.99 (dt, J=1.1, 18.5 Hz,3H).

Step 2

To a solution of 4-bromo-2-(1,1-difluoroethyl)-1-fluorobenzene (450 mg,1.8 mmol) in THF (10.0 mL) was added LDA (2 M, 1.2 mL) at −78° C. Themixture was stirred at −78° C. for 1 h. Then DMF (165 mg, 2.2 mmol,173.8 uL) was added and stirred for 1 h at −78° C.

The mixture was poured into Sat NH₄Cl (10.0 mL) and extracted with ethylacetate (10.0 mL×3). The combined organic layers were washed with brine(10.0 mL×3), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=I/O to 10/1) toafford 5-bromo-3-(1,1-difluoroethyl)-2-fluorobenzaldehyde (0.4 g, 1.5mmol, 79.5% yield). ¹H NMR (CHLOROFORM-d, 400 MHz): δ 10.33 (s, 1H),8.07 (dd, J=2.4, 5.5 Hz, 1H), 7.92 (dd, J=2.4, 6.4 Hz, 1H), 2.05 (t,J=18.6 Hz, 3H)

Step 3

To a solution of guanidine (181 mg, 1.5 mmol, H₂CO₃) and K₂CO₃ (621 mg,4.4 mmol, 4.8 mL) in DMA (10.0 mL) was added a solution of5-bromo-3-(1,1-difluoroethyl)-2-fluorobenzaldehyde (0.4 g, 1.5 mmol) inDMA (1.5 mL). Then the mixture was stirred at 160° C. for 1 h. Themixture was concentrated to get crude residue. And then H₂O (30.0 mL)was added and extracted with Ethyl acetate (30.0 mL×3). The combinedorganic layers were washed with brine (20.0 mL×3), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=I/O to 5/1) to afford6-bromo-8-(1,1-difluoroethyl)quinazolin-2-amine (0.4 g, 1.39 mmol,92.69% yield).

Step 4

To a solution of 6-bromo-8-(1,1-difluoroethyl)quinazolin-2-amine (0.4 g,1.3 mmol) in pyridine (3.5 mL) was added pyridine hydrofluoride (7.7 g,77.7 mmol, 7.00 mL) at −40° C. The mixture was stirred at −40° C. for 15min. Then tert-butyl nitrite (286 mg, 2.7 mmol, 330.2 uL) was added. Themixture was stirred at 20° C. for 12 h. The mixture was poured into icewater and adjusted pH=7 with sat NaHCO₃ extracted with ethyl acetate(50.0 mL×3). The combined organic layers were washed with brine (20.0mL×3), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=I/O to 10:1) toafford 6-bromo-8-(1,1-difluoroethyl)-2-fluoroquinazoline (0.3 g, 1.0mmol, 74.2% yield). ¹H NMR (CHLOROFORM-d, 400 MHz): δ 9.35 (d, J=2.4 Hz,1H), 8.31 (s, 1H), 8.25 (d, J=2.1 Hz, 1H), 2.30 (t, J=19.0 Hz, 3H)

Step 5

To a solution of 6-bromo-8-(1,1-difluoroethyl)-2-fluoroquinazoline (80mg, 274.85 umol) and K₂CO₃ (114 mg, 824.5 umol) in dioxane (2.0 mL) andH₂O (0.2 mL) were added2-chloro-N-(6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)benzenesulfonamide(233 mg, 549.7 umol) and Pd(dppf)Cl₂ (20 mg, 27.4 umol). The mixture wasstirred at 90° C. for 12 h under N₂. The mixture was concentrated to getcrude residue. The residue was purified by prep-TLC to give2-chloro-N-(5-(8-(1,1-difluoroethyl)-2-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide(100 mg, 196.5 umol, 71.4% yield).

Step 6

To a solution of2-chloro-N-(5-(8-(1,1-difluoroethyl)-2-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide(50 mg, 98.2 umol) in n-BuOH (2.0 mL) was added cyclohexane-1,4-diamine(22. mg, 196.5 umol) and DIEA (38 mg, 294.7 umol, 51.3 uL). The mixturewas stirred at 100° C. for 12 h. The mixture was concentrated to getcrude residue. The residue was purified by prep-HPLC (FA condition) toaffordN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-(1,1-difluoroethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(8.0 mg, 12.1 umol, 12.4% yield, FA). M+H⁺=603.1 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) 9.01 (s, 1H), 8.55 (br s, 1H), 8.31 (d, J=7.3 Hz, 1H),8.04 (s, 1H), 7.88 (s, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.59-7.55 (m, 2H),7.55-7.46 (m, 1H), 6.63 (d, J=8.1 Hz, 1H), 3.90 (br s, 1H), 3.65 (s,3H), 3.22-3.09 (m, 1H), 2.34-2.19 (m, 5H), 2.14 (br d, J=12.2 Hz, 2H),1.68-1.42 (m, 4H).

Example 25: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-(trifluoromethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(134)

Step 1

To a solution of 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (5.0 g,20.5 mmol, 2.9 mL) in THF (50.0 mL) was added LDA (2 M, 13.3 mL) at −78°C. The mixture was stirred at −78° C. for 1 hr. Then DMF (1.8 g, 24.6mmol, 1.9 mL) was added and stirred for 1 h at −78° C. The mixture waspoured into Sat NH₄Cl (20.0 mL) and extracted with ethyl acetate (20.0mL×3). The combined organic layers were washed with brine (20.0 mL×3),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=I/O to 10/1) to afford5-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (4 g, 14.7 mmol, 71.7%yield). ¹H NMR (CHLOROFORM-d, 400 MHz): δ 10.35 (s, 1H), 8.19 (dd,J=2.5, 5.4 Hz, 1H), 7.98 (dd, J=2.1, 6.1 Hz, 1H).

Step 2

To a solution of guanidine (1.3 g, 11.0 mmol, H₂CO₃) and K₂CO₃ (4.5 g,33.2 mmol) in DMA (60.0 mL) was added a solution of5-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (3.0 g, 11.0 mmol) inDMA (9.0 mL). Then the mixture was stirred at 160° C. for 1 h. Themixture was concentrated to get crude residue. And then H₂O (30.0 mL)was added and extracted with ethyl acetate (30.0 mL×3). The combinedorganic layers were washed with brine (20.0 mL×3), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=I/O to 5/1) to afford6-bromo-8-(trifluoromethyl)quinazolin-2-amine (1.6 g, 4.6 mmol, 42.0%yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 9.19 (s, 1H), 8.34 (d, J=2.2 Hz,1H), 8.12 (d, J=2.0 Hz, 1H), 7.42 (s, 2H).

Step 3

To a solution of 6-bromo-8-(trifluoromethyl)quinazolin-2-amine (1.5 g,5.1 mmol) in pyridine (13.0 mL) was added pyridine hydrofluoride (28.6g, 288.5 mmol, 26.0 mL) at −40° C. The mixture was stirred at −40° C.for 15 min. Then tert-butyl nitrite (1.0 g, 10.2 mmol, 1.2 mL) wasadded. The mixture was stirred at 20° C. for 12 h. The mixture waspoured into ice water and adjusted pH=7 with sat NaHCO₃, extracted withethyl acetate (50.0 mL×3). The combined organic layers were washed withbrine (20.0 mL×3), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=I/O to 10/1) toafford 6-bromo-2-fluoro-8-(trifluoromethyl)quinazoline (1.0 g, 3.3 mmol,64.9% yield). M+H⁺=294.9 (LCMS).

Step 4

To a solution of 6-bromo-2-fluoro-8-(trifluoromethyl)quinazoline (0.4 g,1.3 mmol) in n-BuOH (20.0 mL) were added tert-butylN-(4-aminocyclohexyl)carbamate (349 mg, 1.6 mmol) and DIEA (350 mg, 2.7mmol, 472.3 uL). The mixture was stirred at 100° C. for 12 h. Themixture was cooled to 25° C. and filtered. The cake was washed withPetroleum ether (50.0 mL) to afford tert-butyl((1r,4r)-4-((6-bromo-8-(trifluoromethyl)quinazolin-2-yl)amino)cyclohexyl)carbamate (0.5 g, 1.0 mmol, 74.6% yield). M+H⁺=491.2 (LCMS).

Step 5

To a solution of tert-butyl((1r,4r)-4-((6-bromo-8-(trifluoromethyl)quinazolin-2-yl)amino)cyclohexyl)carbamate (0.3 g, 613.0 umol) and K₂CO₃ (254.2 mg, 1.8 mmol) in dioxane(6.0 mL) and H₂O (0.6 mL) were added2-chloro-N-(6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)benzenesulfonamide(312 mg, 735.7 umol) and Pd(dppf)Cl₂ (45 mg, 61.3 umol). The mixture wasstirred at 90° C. for 12 h under N₂. The mixture was concentrated to getcrude residue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=I/O to 1/1) to give tert-butyl((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-2-methoxypyridin-3-yl)-8-(trifluoromethyl)quinazolin-2-yl)amino)cyclohexyl)carbamate(0.3 g, 171.1 umol, 27.9% yield). M+H⁺=707.1 (LCMS).

Step 6

A solution of tert-butyl((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-2-methoxypyridin-3-yl)-8-(trifluoromethyl)quinazolin-2-yl)amino)cyclohexyl)carbamate(0.3 g, 424.2 umol) in DCM (2.0 mL) and TFA (1.0 mL) was stirred at 25°C. for 10 min. The mixture was concentrated to get crude residue. Theresidue was dissolved in MeOH (2.0 mL) and basified pH to 8 with NH₃.H₂O(25% solution), concentrated to give a residue. The residue was purifiedby prep-HPLC (FA condition) to affordN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-(trifluoromethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(141.4 mg, 215.5 umol, 50.8% yield, FA). M+H⁺=607.2 (LCMS); ¹H NMR(METHANOL-d₄, 400 MHz) 9.06 (s, 1H), 8.53 (s, 1H), 8.32 (dd, J=1.2, 7.8Hz, 1H), 8.15 (s, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H),7.63-7.55 (m, 2H), 7.55-7.47 (m, 1H), 6.66 (d, J=7.9 Hz, 1H), 3.99-3.83(m, 1H), 3.68 (s, 3H), 3.23-3.08 (m, 1H), 2.31 (br d, J=8.8 Hz, 2H),2.14 (br d, J=12.6 Hz, 2H), 1.70-1.38 (m, 4H).

Example 26: Synthesis ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(115)

The title compound was synthesized according to the synthetic procedurereported for the preparation ofN-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-(trifluoromethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(18.8 mg, 30.8 umol, 20.1% yield, FA). M+H⁺=553.2 (LCMS); ¹H NMR(METHANOL-d₄, 400 MHz) δ 8.95 (s, 1H), 8.55 (br s, 1H), 8.31 (d, J=7.6Hz, 1H), 7.70-7.61 (m, 3H), 7.61-7.55 (m, 2H), 7.54-7.48 (m, 1H), 6.63(d, J=7.9 Hz, 1H), 4.04-3.92 (m, 1H), 3.65 (s, 3H), 3.22-3.09 (m, 1H),2.53 (s, 3H), 2.31 (br d, J=11.5 Hz, 2H), 2.13 (br d, J=11.9 Hz, 2H),1.68-1.39 (m, 4H).

Example 27: Synthesis of2-chloro-N-(5-(2-((4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)amino)-8-ethylquinazolin-6-yl)-6-ethylpyridin-2-yl)benzenesulfonamide(136)

Step 1

To a solution of tert-butyl N-(1-amino-4-bicyclo[2.2.2]octanyl)carbamate(500 mg, 2.1 mmol) and (HCHO)n (562 mg, 6.2 mmol) in MeOH (15.0 mL) wasadded AcOH (125 mg, 2.1 mmol, 119 uL) to adjust pH to 5 and then themixture was stirred for 2 h at 30° C. Then NaBH₃CN (523 mg, 8.3 mmol)was added. The mixture was stirred at 45° C. for 12 h. The reaction wasconcentrated to give a residue. The residue was dissolved in saturatedNaHCO₃ (15.0 mL) and extracted with ethyl acetate (10 mL×3). Thecombined organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated to give tert-butyl(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)carbamate (550 mg, crude).

Step 2

The mixture of tert-butyl(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)carbamate (500 mg, 1.8 mmol)in HCl/MeOH (4M, 10.0 mL) was stirred at 20° C. for 0.5 h. The reactionwas concentrated to give N1,N1-dimethylbicyclo[2.2.2]octane-1,4-diamine(380 mg, crude, HCl).

Step 3

To a solution of2-chloro-N-(6-ethyl-5-(8-ethyl-2-fluoroquinazolin-6-yl)pyridin-2-yl)benzenesulfonamide(50 mg, 106.2 umol) in n-BuOH (4.0 mL) was added DIEA (110 mg, 849.4umol, 147.9 uL) and N1,N1-dimethylbicyclo[2.2.2]octane-1,4-diamine (65mg, 318.5 umol, HCl). The mixture was stirred at 120° C. for 12 h. Thereaction was concentrated to give a residue. The residue was purified byprep-HPLC (HCl condition) and then was purified by prep-HPLC (FAcondition) to afford2-chloro-N-(5-(2-((4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)amino)-8-ethylquinazolin-6-yl)-6-ethylpyridin-2-yl)benzenesulfonamide(2.1 mg, 2.9 umol, 2.8% yield, FA). M+H⁺=619.3 (LCMS); ¹H NMR (400 MHz,METHANOL-d₄) δ 8.87 (s, 1H), 8.45 (br s, 2H), 8.15 (d, J=7.5 Hz, 1H),7.51 (br d, J=8.8 Hz, 1H), 7.45 (d, J=3.8 Hz, 2H), 7.43-7.36 (m, 3H),7.00 (br d, J=8.3 Hz, 1H), 2.99 (q, J=7.3 Hz, 2H), 2.71 (s, 6H), 2.53(q, J=7.5 Hz, 2H), 2.32-2.22 (m, 6H), 2.01-1.88 (m, 6H), 1.23 (t, J=7.5Hz, 3H), 0.99 (br t, J=7.5 Hz, 3H).

Example 27A: Synthesis of (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine

The title compound was synthesized according to the synthetic procedurereported for the preparation ofN1,N1-dimethylbicyclo[2.2.2]octane-1,4-diamine (8.3 g, 46.4 mmol, 99.6%yield, HCl). ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (br s, 1H), 8.31 (br s,3H), 3.62-3.36 (m, 1H), 3.15-3.03 (m, 1H), 2.96 (br d, J=4.0 Hz, 1H),2.65 (d, J=4.9 Hz, 6H), 2.09 (br s, 4H), 1.65-1.31 (m, 4H).

Example 27B: Synthesis of (1s,4s)-N1,N1-dimethylcyclohexane-1,4-diamine

The title compound was synthesized according to the synthetic procedurereported for the preparation ofN1,N1-dimethylbicyclo[2.2.2]octane-1,4-diamine (1.7 g, crude, HCl). ¹HNMR (400 MHz, METHANOL-d₄) δ 3.53 (br s, 1H), 3.41-3.33 (m, 1H), 2.89(s, 6H), 2.13-1.88 (m, 9H).

Example 28: Synthesis ofN-(5-(2-(((1s,4s)-4-aminocyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(146)

Step 1

A mixture of 6-bromo-2-fluoro-8-methylquinazoline (500 mg, 2.0 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (632 mg, 2.4mmol), KOAc (610 mg, 6.22 mmol), Pd(dppf)Cl₂ (151 mg, 207.4 umol) indioxane (20.0 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 90° C. for 12 h under N₂ atmosphere. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=100/1 to 10/1) to afford2-fluoro-8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline(590 mg, 1.9 mmol, crude). M+H⁺=289.2 (LCMS).

Step 2

A mixture of2-fluoro-8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline(349 mg, 1.2 mmol),N-(5-bromo-3-fluoro-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(400 mg, 1.0 mmol), K₂CO₃ (419 mg, 3.0 mmol), Pd(dppf)Cl₂ (73 mg, 101umol) in dioxane (15.0 mL) and H₂O (1.5 mL) was degassed and purged withN₂ for 3 times, and then the mixture was stirred at 90° C. for 12 hunder N₂ atmosphere. The reaction mixture was concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=10/1 to 1/1) to afford2-chloro-N-(3-fluoro-5-(2-fluoro-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide(450 mg, 802 umol, 79.3% yield). M+H⁺=477.2 (LCMS).

Step 3

To a solution of (1s,4s)-cyclohexane-1,4-diamine (237 mg, 1.5 mmol, HCl)in n-BuOH (7.0 mL) was added DIEA (325 mg, 2.5 mmol, 438.3 uL) and2-chloro-N-(3-fluoro-5-(2-fluoro-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide(150 mg, 314.5 umol). The mixture was stirred at 100° C. for 24 h. Thereaction mixture was concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (FA condition) to affordN-(5-(2-(((1s,4s)-4-aminocyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(50.0 mg, 80.2 umol, 25.5% yield, FA). M+H⁺=571.2 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 8.97 (s, 1H), 8.56 (br s, 1H), 8.31 (d, J=7.6 Hz,1H), 7.68 (s, 2H), 7.62-7.54 (m, 3H), 7.54-7.45 (m, 1H), 4.21 (br s,1H), 3.46 (s, 3H), 3.28 (br s, 1H), 2.53 (s, 3H), 2.13 (br d, J=9.8 Hz,2H), 2.02-1.69 (m, 6H).

Example 29: Synthesis ofN-(5-(2-(((1s,4s)-4-aminocyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(138)

The title compound was synthesized according to the synthetic procedurereported for the preparation ofN-(5-(2-(((1s,4s)-4-aminocyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(40.8 mg, 67.2 umol, 21.4% yield, FA). M+H⁺=553.1 (LCMS); ¹HNMR (400MHz, METHANOL-d₄) δ 8.92 (s, 1H), 8.44 (br s, 1H), 8.36-8.22 (m, 1H),7.68-7.40 (m, 6H), 6.62 (d, J=7.9 Hz, 1H), 4.19 (br s, 1H), 3.63 (s,3H), 3.29-3.22 (m, 1H), 2.50 (s, 3H), 2.17-2.02 (m, 2H), 2.01-1.69 (m,6H).

Example 30: Synthesis ofN-(5-(2-(((1s,4s)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(140)

Step 1

To a solution of 6-bromo-8-ethylquinazolin-2-amine (10.0 g, 39.6 mmol)in Py (100 mL) was added pyridine; hydrofluoride (220.0 g, 2.2 mol,200.0 mL) at −40° C. The mixture was stirred at −40° C. for 15 min. Thentert-butyl nitrite (8.1 g, 79.3 mmol, 9.4 mL) was added. The mixture wasstirred at 20° C. for 12 h. The mixture was poured into ice water andadjusted pH=7 with sat. NaHCO₃, extracted with EtOAc (500.0 mL×3). Thecombined organic layers were washed with brine (200.0 mL×3), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂) togive 6-bromo-8-ethyl-2-fluoroquinazoline (11.4 g, 40.8 mmol, 55.4%yield). M+H⁺=257.0 (LCMS); ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.26 (d,J=2.6 Hz, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.87 (d, J=1.1 Hz, 1H), 3.18 (q,J=7.5 Hz, 2H), 1.37 (t, J=7.5 Hz, 3H).

Step 2

A mixture of2-chloro-N-(6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)benzenesulfonamide(399 mg, 940.8 umol), 6-bromo-8-ethyl-2-fluoroquinazoline (200 mg, 784.0umol), Pd(dppf)Cl₂ (57 mg, 78.4 umol), and K₂CO₃ (325 mg, 2.3 mmol) indioxane (6.0 mL) and H₂O (0.6 mL) was degassed and purged with N₂ for 3times, and then the mixture was stirred at 90° C. for 12 h under N₂atmosphere. The reaction mixture was concentrated under reduced pressureto give a residue. The residue was purified by column chromatography(SiO₂) to give2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide(430 mg, crude).

Step 3

To a solution of (1s,4s)-cyclohexane-1,4-diamine (144 mg, 1.2 mmol, HCl)in n-BuOH (6.0 mL) was basified pH to 8 by DIEA. Then the mixture wasadded2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide(200 mg, 422.9 umol) and DIEA (327 mg, 2.5 mmol, 441.9 uL) and stirredat 100° C. for 12 h. The reaction mixture was concentrated under reducedpressure to give a residue. The residue was purified by pre-HPLC (FAcondition) to affordN-(5-(2-(((1s,4s)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide(121.7 mg, 196.0 umol, 46.3% yield, FA). M+H⁺=567.2 (LCMS); ¹H NMR (400MHz, METHANOL-d₄) δ 8.98 (s, 1H), 8.55 (s, 1H), 8.36-8.26 (m, 1H),7.71-7.45 (m, 6H), 6.63 (d, J=8.2 Hz, 1H), 4.20 (br s, 1H), 3.65 (s,3H), 3.26 (br dd, J=3.6, 9.8 Hz, 1H), 3.03 (q, J=7.5 Hz, 2H), 2.21-2.06(m, 2H), 1.98-1.71 (m, 6H), 1.29 (t, J=7.5 Hz, 3H).

Example 31: Synthesis of2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide(144)

Step 1

To a solution of tert-butyl (1-methyl-4-oxocyclohexyl)carbamate (900 mg,4 mmol) in EtOH (20.0 mL) was added phenylmethanamine (509 mg, 4.7 mmol,517.9 uL) and AcOH (238 mg, 4 mmol, 226.5 uL) at 0° C. The resultingmixture was stirred at 0° C. for 15 min. Follow by successive additionof NaBH₃CN (498 mg, 7.9 mmol), the mixture was stirred at 20° C. for 12h. The reaction was concentrated to give a residue. The residue wasdissolved in saturated aqueous NaHCO₃ (20.0 mL) and extracted with ethylacetate (20.0 mL×3). The combined organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated to give tert-butyl(4-(benzylamino)-1-methylcyclohexyl)carbamate (1.3 g, crude).

Step 2

To a solution of tert-butyl(4-(benzylamino)-1-methylcyclohexyl)carbamate (1.2 g, 3.7 mmol) in DMF(20.0 mL) was added K₂CO₃ (1.6 g, 11.3 mmol) and bromomethylbenzene (773mg, 4.5 mmol, 537.1 uL). The mixture was stirred at 40° C. for 12 h. Thereaction was quenched with H₂O (30.0 mL) and extracted with ethylacetate (20 mL×3). The combined organic was washed with brine (20 mL×3),dried over anhydrous Na₂SO₄, filtered and concentrated to give aresidue. The residue was purified by flash silica gel chromatography(SiO₂) to afford tert-butyl(4-(dibenzylamino)-1-methylcyclohexyl)carbamate (1.5 g, 3.4 mmol, 90%yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.42-7.35 (m, 4H), 7.34-7.29(m, 4H), 7.26-7.19 (m, 2H), 3.69-3.63 (m, 4H), 2.60-2.46 (m, 1H), 2.13(br d, J=11.9 Hz, 1H), 1.94 (br d, J=9.3 Hz, 1H), 1.84-1.66 (m, 2H),1.61-1.50 (m, 3H), 1.47-1.39 (m, 9H), 1.36-1.24 (m, 4H).

Step 3

The mixture of tert-butyl(4-(dibenzylamino)-1-methylcyclohexyl)carbamate (500 mg, 1.2 mmol) inHCl/MeOH (4M, 10.0 mL) was stirred at 20° C. for 1 h. The reaction wasconcentrated to give N¹,N¹-dibenzyl-4-methylcyclohexane-1,4-diamine (400mg, crude, HCl).

Step 4

To a solution of N¹,N¹-dibenzyl-4-methylcyclohexane-1,4-diamine (350 mg,1 mmol, HCl) in MeOH (10.0 mL) was added TEA to basify pH to 7 and then(HCHO)n (274 mg, 3 mmol) was added. AcOH (61 mg, 1 mmol, 58 uL) wasadded to adjust pH to 5 and then the mixture was stirred at 60° C. for 2h. NaBH₃CN (255 mg, 4.1 mmol) was added and the mixture was stirred at60° C. for 12 h. The reaction was concentrated to give a residue. Theresidue was dissolved in saturated NaHCO₃ (10.0 mL) and extracted withethyl acetate (10.0 mL×3). The combined organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated to giveN⁴,N⁴-dibenzyl-N¹,N¹,1-trimethylcyclohexane-1,4-diamine (330 mg, crude).

Step 5

To a solution of N⁴,N⁴-dibenzyl-N¹,N¹,1-trimethylcyclohexane-1,4-diamine(330 mg, 980.6 umol) in THF (10.0 mL) and AcOH (0.1 mL) was addedPd(OH)₂/C (400 mg, 980.6 umol, 10% Pd basis) under N₂ atmosphere. Thesuspension was degassed and purged with H₂ for 3 times. The mixture wasstirred under H₂ (50 Psi) at 50° C. for 12 h. The reaction was filteredand concentrated to give N¹,N¹,1-trimethylcyclohexane-1,4-diamine (150mg, crude).

Step 6

To a solution of2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide(30 mg, 61.1 umol) in n-BuOH (3.0 mL) was added DIEA (63 mg, 488.9 umol,85.2 uL) and N¹,N¹,1-trimethylcyclohexane-1,4-diamine (38 mg, 244.4umol). The mixture was stirred at 120° C. for 12 h. The reaction wasconcentrated to give a residue. The residue was purified by prep-HPLC(FA condition) to afford2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide(3.7 mg, 5.4 umol, 8.9% yield, FA). M+H⁺=627.3 (LCMS); ¹H NMR (400 MHz,METHANOL-d₄) δ 8.98 (br s, 1H), 8.53 (br s, 1H), 8.32 (br d, J=7.8 Hz,1H), 7.69 (s, 2H), 7.62-7.47 (m, 4H), 4.16 (br s, 1H), 3.46 (s, 3H),3.03 (q, J=7.4 Hz, 2H), 2.85 (s, 6H), 2.13-1.92 (m, 6H), 1.86 (br d,J=5.7 Hz, 2H), 1.41 (s, 3H), 1.29 (br t, J=7.4 Hz, 3H); ¹H NMR (400 MHz,DMSO-d₆) δ 8.98 (s, 1H), 8.18-8.12 (m, 1H), 7.66 (s, 2H), 7.44-7.32 (m,4H), 3.99 (br s, 1H), 3.31 (s, 3H), 2.96 (q, J=7.5 Hz, 2H), 2.51 (br s,6H), 2.01-1.75 (m, 6H), 1.58-1.47 (m, 2H), 1.24 (t, J=7.5 Hz, 3H), 1.13(s, 3H).

Example 32: Synthesis of2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide(143)

The title compound was synthesized according to the synthetic procedurereported for the preparation of2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide(6.4 mg, 9.4% yield). M+H⁺=609.3 (LCMS); ¹H NMR (400 MHz, METHANOL-d₄) δ8.94 (s, 1H), 8.33-8.27 (m, 1H), 7.64 (dd, J=1.9, 13.4 Hz, 2H), 7.60 (d,J=8.1 Hz, 1H), 7.58-7.54 (m, 2H), 7.52-7.46 (m, 1H), 6.60 (d, J=7.9 Hz,1H), 4.10 (br t, J=5.3 Hz, 1H), 3.62 (s, 3H), 3.02 (q, J=7.5 Hz, 2H),2.68-2.59 (m, 6H), 2.06-1.89 (m, 6H), 1.73-1.62 (m, 2H), 1.31-1.22 (m,6H).

II. Biological Evaluation Example 1: In Vitro FRET Assay

In vitro FRET assay was performed to evaluate the ability of selectcompounds to inhibit IRE1, the results of which are summarized in Table3. To perform the in vitro FRET assay, 1× complete assay buffer (CAB; 1MDTT, 50 mM sodium citrate pH 7.15, ImM magnesium acetate, 0.02% tween20) was used to dilute SignalChem IRE1a protein to a final concentrationof 2 nM. Selected compounds were serially diluted with DMSO in anon-binding black 384-well plate for a total of 15 ul in each well. 2 ulof the serially diluted compound or DMSO control were then added to newwells containing 98 ul of 1×CAB, for a total volume of 100 ul, 10 ul ofwhich were then transferred to wells of a new plate. 5 ul of the dilutedIRE1a was then added to each well. 5 ul of a 400 mM XBP1 RNA probe wasthen added to each well. Fluorescence was then read over 30 minutes inkinetic mode (485/515 nm).

Two RNA probes were used, XBP1 wildtype (SEQ ID NO: 2) which is able tobe spliced by active IRE1a or XBP1 mutant (SEQ ID NO: 3) which is unableto be spliced. Each probe contained a 5′ 6-FAM modification and a 3′IOWA Black FQ modification.

A second FRET assay was performed to assess ATP-mediated inhibition. Inthis case, compounds and IRE1a were prepared and combined as discussedabove, with the addition of ATP up to 1 mM final concentration. Thismixture was incubated at room temperature for 60 minutes and then 5 ulof 400 nM XBP1 wildtype or mutant RNA probe was added. Plates were thenread over 30 minutes in kinetic mode (485/515 nm).

TABLE 3 Compound Ref. No. Mean IC₅₀ 1 B 2 A  3; Formic Acid A 4 A 5 A 6A 7 B 8 B 9 A 10  A 11  A 12  D 13  D 14; Formic Acid D 15; Formic AcidD 16; Formic Acid A 17; Formic Acid D 18; Formic Acid A 19; Formic AcidA 20; Formic Acid A 21; Formic Acid A 22; Formic Acid B 23; Formic AcidA 24; Formic Acid A 25; Formic Acid A 26; Formic Acid A 27; Formic AcidA 28; Formic Acid A 29; Formic Acid A 30; Formic Acid C 31; Formic AcidD 32; Formic Acid A 33; Formic Acid A 34; Formic Acid A 35; Formic AcidA 36; Formic Acid A 37; HCl      A 38; Formic Acid A 39; Formic Acid A40; Formic Acid A 41; Formic Acid A 42; Formic Acid A 43; Formic Acid A44; Formic Acid A 45; Formic Acid C 46; Formic Acid A 47; Formic Acid A48; Formic Acid A 49; Formic Acid A 50; Formic Acid A 51; Formic Acid A52; Formic Acid A 53; Formic Acid A 54; Formic Acid A 55; Formic Acid A56; Formic Acid A 57; Formic Acid A 58; Formic Acid B 59; Formic Acid B60; Formic Acid A 62; Formic Acid A 63; Formic Acid A 65; Formic Acid A66; Formic Acid A 67; Formic Acid A 68; Formic Acid A 69; Formic Acid A70; Formic Acid A 71; Formic Acid A 72; Formic Acid A 73; Formic Acid A74; Formic Acid A 75; Formic Acid A 76; Formic Acid A 77; Formic Acid A78; Formic Acid A 79; Formic Acid A 80; Formic Acid A 81; Formic Acid A82; Formic Acid A 83; Formic Acid B 84; Formic Acid A 85; Formic Acid A86; Formic Acid A 87; Formic Acid A 88; Formic Acid A 89; Formic Acid A90; Formic Acid A 92; Formic Acid A 93; Formic Acid A 94; Formic Acid A96; Formic Acid A 98; Formic Acid A 100; Formic Acid  A 101; FormicAcid  B 102; Formic Acid  A 103; Formic Acid  A 104; Formic Acid  A 105;Formic Acid  A 106; Formic Acid  A 107; Formic Acid  A 109; Formic Acid A 110; Formic Acid  A 111; Formic Acid  A 112; Formic Acid  A 113;Formic Acid  A 114; Formic Acid  B 115; Formic Acid  A 120; Formic Acid A 121; Formic Acid  A 123; Formic Acid  A 129; Formic Acid  A 134;Formic Acid  A 136; Formic Acid  A 138; Formic Acid  A 140; Formic Acid A 143; Formic Acid  B 144; Formic Acid  C 146; Formic Acid  A Note:Biochemical assay Mean IC₅₀ data are designated within the followingranges: A: ≤5 nM; B: >5 nM to ≤50 nM; C: >50 nM to ≤100 nM; and D: >100nM.

Example 2: In Vitro Luciferase Assay

Compounds disclosed herein were assessed for disruption of IRE1signaling using a IRE1a Endoribonuclease Nanoluciferase Assay. Briefly,2.5×10⁶ 293T cells were seeded in a 10 cm² tissue culture plate. About24 hours later, the cells were transfected with Effectene. In a 15 mLTube, the following was added: 2 ug XBP1 luciferase reporter plasmid(PGK-Luc2-P2A-XBP1u-Nanoluciferase-PEST); 300 ul EC buffer; and 16 ulEnhancer, followed by incubation at room temp for 5 minutes. Next, 60 ulEffectene (Qiagen 301427) was added, followed by incubation at roomtemperature for 10 minutes. 2.6 mL cDMEM media was added. Old media wasaspirated from the cells, followed by addition of 7 mL fresh media. Fulltransfection mixture was added dropwise to cells. Cells were incubatedfor 6 hours, followed by trypsinization, centrifugation and resuspensionin 11 mL media. 100 uL of cells were plated per a well in a 96 wellplate. A day later, ER stressors of choice +/− inhibitors were added. Toharvest, media was aspirated from cells completely, then 50 uL 1×passive lysis buffer (Promega: E1941) was added per well and put onshaker (300 rpm) for 30 minutes at room temperature. Cells werecentrifuged, and 15 uL sample per well was added to a new, opaque white384 well plate (Corning 3570). 15 uL OneGlo (nanoluciferase kit, PromegaN1630) was added. Plates were spun down, placed on shaker (300 rpm) for10 minutes. Plates were read on luminometer, 1000 ms integration timeper well. 15 uL Stop and Glo (nanoluciferase kit) was added. Plates werespun down, placed on shaker (300 rpm) for 10 minutes. Plates were readon luminometer, 1000 ms second integration time per well. Recordings areprovided below in Table 4.

TABLE 4 Compound Ref. No. Mean EC₅₀ 1 D 2 D  3; Formic Acid B 4 C 5 D 6C 11  D 16; Formic Acid A 18; Formic Acid A 19; Formic Acid A 20; FormicAcid C 21; Formic Acid B 22; Formic Acid D 23; Formic Acid A 24; FormicAcid A 25; Formic Acid A 26; Formic Acid A 27; Formic Acid A 28; FormicAcid A 29; Formic Acid D 32; Formic Acid A 33; Formic Acid A 34; FormicAcid B 35; Formic Acid A 37; HCl      A 44; Formic Acid A 46; FormicAcid A 47; Formic Acid B 48; Formic Acid B 51; Formic Acid C 52; FormicAcid A 53; Formic Acid A 54; Formic Acid B 55; Formic Acid A 56; FormicAcid A 57; Formic Acid A 58; Formic Acid A 59; Formic Acid C 60; FormicAcid A 62; Formic Acid B 65; Formic Acid B 66; Formic Acid C 67; FormicAcid B 68; Formic Acid C 69; Formic Acid A 70; Formic Acid A 71; FormicAcid A 72; Formic Acid D 73; Formic Acid A 74; Formic Acid A 75; FormicAcid D 76; Formic Acid B 77; Formic Acid B 78; Formic Acid A 79; FormicAcid B 80; Formic Acid D 81; Formic Acid A 82; Formic Acid B 83; FormicAcid C 84; Formic Acid B 85; Formic Acid D 86; Formic Acid C 87; FormicAcid A 88; Formic Acid A 89; Formic Acid D 90; Formic Acid B 92; FormicAcid D 93; Formic Acid A 94; Formic Acid A 98; Formic Acid A 100; FormicAcid  C 102; Formic Acid  C 103; Formic Acid  A 104; Formic Acid  C 107;Formic Acid  A 109; Formic Acid  A 110; Formic Acid  A 111; Formic Acid C 112; Formic Acid  B 113; Formic Acid  B 115; Formic Acid  A 120;Formic Acid  A 121; Formic Acid  A 123; Formic Acid  A 129; Formic Acid A 134; Formic Acid  A 136; Formic Acid  A 138; Formic Acid  C Note:Biochemical assay Mean EC₅₀ data are designated within the followingranges: A: ≤5 nM; B: >5 nM to ≤50 nM; C: >50 nM to ≤100 nM; and D: >100nM.

Example 3: Growth Assay

A growth assay was performed to evaluate the compounds disclosed hereinfor cytotoxicity. Briefly, 5,000,000 293T cells were resuspended in 18mL of cDMEM for a final concentration of 277,777 cells/mL. 180 uL(50,000 cells) cDMEM was seeded per well in a 96 well flat bottom plateas shown in Table 5, with “media” wells left unfilled. In a separate 96well dilution plate, 199 uL cDMEM and 1 uL of DMSO or any one of thecompounds disclosed herein (shown as Test Compound 1, 2, 3, 4, 5, or 6below) were added to wells A4, A8, C4, C8, E4, E8, G4, and G8. 133.3 uLcDMEM was added to wells 1, 2, 3, 5, 6, and 7 in rows A, C, E and G ofthe dilution plate. Compounds were serially diluted leftwards inthreefold dilutions (66.7 uL into 133.3 uL cDMEM). 20 uL of eachdilution was transferred in duplicate (duplicates in vertical pairedwells) to the cells plated in the 96-well plate shown in Table 5, to thetotal concentrations shown below. 200 uL cDMEM was added to media wells(wells G5-H8). The plate was then placed in a humidified chamber for a 2day incubation, and then photographed (media was more yellow in wellswith potent cell growth). Absorbance was then measured at about 535 nM(lower for more acidic media) and about 450 nM (higher for more acidicmedia). The results of the growth assay as shown in Table 6.

TABLE 5 1 2 3 4 5 6 7 8 A Test Test Com- Com- pound 1 pound 5 B C TestTest Com- Com- pound 2 pound 6 D E Test DMSO Com- pound 3 F G Test mediaCom- only pound 4 H Conc 0.185 0.556 1.667 5 0.185 0.5556 1.667 5 (uM)

TABLE 6 % % % % Compound Ref. Growth at Growth at Growth at Growth No.0.185 uM 0.5556 uM 1.667 uM at 5 uM  3; Formic Acid D D C A 16; FormicAcid D D D B 18; Formic Acid D D C A 19; Formic Acid D D C A 20; FormicAcid D D D C 21; Formic Acid D D D B 22; Formic Acid D D D A 23; FormicAcid D C C D 24; Formic Acid D D C C 25; Formic Acid D D D D 27; FormicAcid D D C B 28; Formic Acid D D C B 29; Formic Acid D D D D 32; FormicAcid D D C B 33; Formic Acid D D D C 34; Formic Acid D D D A 35; FormicAcid D D C B 37; HCl      n/a D C B 46; Formic Acid D D D D  3; FormicAcid D D C A 16; Formic Acid D D D B 18; Formic Acid D D C A 19; FormicAcid D D C A 20; Formic Acid D D D C 21; Formic Acid D D D B 22; FormicAcid D D D A 52; Formic Acid D D D C 55; Formic Acid D D D D 65; FormicAcid D D D C 67; Formic Acid D D C C 69; Formic Acid n/a D C C 71;Formic Acid D D C B Note: % Growth data are designated within thefollowing ranges: A: ≤25%; B: >25% to ≤50%; C: >50% to ≤75%; D: >75% to≤100%;

Example 4: Microsome Stability Assay

The formic acid salt of Compound 3 was tested under the microsomestability assay outlined below. Test compounds were incubated at 37° C.with liver microsomes (pooled from multiple donors) at 1 NM in thepresence of a NADPH regenerating system at 0.5 mg/ml microsomal protein.Positive controls included Testosterone (3A4 substrate), Propafenone(2D6) and Diclofenac (2C9), which were incubated with microsomes in thepresence of an NADPH regenerating system. At time points (0, 5, 10, 20,30 and 60 minutes), samples were removed and immediately mixed with coldacetonitrile containing internal standard (IS). Test compounds incubatedwith microsomes without the NADPH regenerating system for 60 min wasalso included. A single point for each test condition (n=1) wasobtained, and samples were analyzed by LC/MS/MS. Disappearance of thetest compound was assessed based on peak area ratios of analyte/IS (nostandard curve).

The results of the microsome stability assay are shown below in thefollowing table:

TABLE 7 Human Liver Microsome (HLM) T_(1/2) 47.5 min Human CI 29.2uL/min/mg HLM Remaining at 60 min 44% Mouse Liver Microsome T_(1/2) 43.5min Mouse Liver Microsome CI 31.9 uL/min/mg Mouse Liver MicrosomeRemaining at 60 min 41% No issues with plasma stability were observed.

Example 5: ELISA Assay

Total human or mouse CD4 T cells are isolated by negative selection withMiltenyi MACS beads. Mouse CD4 T cells are isolated from mouse spleenwhile human CD4 T cells were isolated from human PBMCs. CD4 T cells arewashed and then mixed with CD3/CD28 activator Dynabeads at 8 pm. After a36 hour incubation, select IRE1a inhibitor compounds or IRE1a inhibitorcontrols are added and incubated for 2 hours.

After the two hour incubation, mouse or human cell-free malignantascites supernatants or cRPMI control are added. After a 10 hourincubation, supernatants are isolated and used in an IFN-g ELISA assay.Trizol is added to each ELISA well containing T Cells for isolating RNA.ELISA assay is performed with the eBioscience Ready-Set-Go IFN-g ELISAkit according to the manufacturer's recommended protocol.

Example 6: T Cell Metabolism Assay

Total human or mouse CD4 T cells are isolated by negative selection withMiltenyi MACS beads. Mouse CD4 T cells are isolated from mouse spleenwhile human CD4 T cells are isolated from human PBMCs. One and a halfmillion CD4 T cells are washed and then mixed with CD3/CD28 activatorDynabeads at a 1:1 bead:cell ratio and plated in complete RPMI in a 6well plate. After a 24 hour incubation, select IRE1a inhibitor compoundsor IRE1a inhibitor control compounds are added and incubated for 2hours. After the two hour incubation, mouse or human cell-free malignantascites supernatants or cRPMI control are added. After a 16 hourincubation, the dynabeads are removed by magnetic separation andmitochondrial oxygen consumption rate (OCR) and glycolytic extracellularacidification rate (ECAR) is measured with the Seahorse XFe96 Analyzer(Agilent). Samples are assayed in triplicate with 150,000 viable cellsplated in each well of the assay plate. Supernatants are additionallyisolated and used in downstream IFN-g ELISA assays. IRE1a activity isalso measured by quantifying XBP1 splicing with quantitative PCR or byintracellular flow cytometric staining with an XBP1s-specific monoclonalantibody (clone: Q3-695; BD Pharmingen).

Example 7: DC Lipid Accumulation Assay

Approximately 3×10⁶ bone marrow cells (after RBC lysis) are seeded in 10mL cRPMI with 20 ng/mL GM-CSF in a petri dish. On culture day 3, 10 mLof cRPMI+20 ng/mL GM-CSF is added. On culture day 6, non-adherent cellsfrom each plate are collected and resuspended in 20 mL of fresh cRPMI+20ng/mL GM-CSF. On culture day 7, suspension cells are harvested, counted,and the resuspended at 500,000 cells per 180 microliters in freshcRPMI+20 ng/mL GM-CSF+110% final concentration of IRE1a inhibitorcompounds or DMSO as a control. 180 microliters of cell suspension areadded to each well of a 96 well flat bottom TC-treated plate andincubated for 2 hours. 20 ul of 10×LPS (1 ug/mL) prepared in cRPMI+20ng/mL GM-CSF is added to indicated wells and incubated for another 6hours. Cells are spun down and supernatant was stored in a new 96-wellV-bottom plate. 200 microliters of trizol is added to pelleted cells forsubsequent RNA analysis.

Example 8: Bioavailability Studies

FIG. 3 depicts the mean plasma concentration of compound 3 (left) afterintravenous (IV, lmg/kg), oral (PO, 25 mg/kg), and intraperitoneal (IP,25 mg/kg) dosing and compound 37 (right) after intravenous (IV, lmg/kg),oral (PO, 30 mg/kg), and intraperitoneal (IP, 30 mg/kg) dosing.

Example 9: Suppression of XBP1 Splicing by Compound 3

FIG. 4 shows the results of the suppression of XBP1 splicing by Compound3. Mice were injected with 0.25 mg/kg tunicamycin dissolved in DMSO: PBSat a ratio of 1:3. After 2 hours, the mice were injected with 10 mg/kgof Compound 3 dissolved in water or water alone as a vehicle control.After an additional 4 hours, the animals were euthanized, liversdissected out, and 2-3 mm³ liver pieces are flash frozen on dry ice.Liver pieces were then thawed in Trizol on ice, homogenized for 3minutes with a bead mill at medium-high speed. RNA was then extractedfrom the Trizol solution according to the manufacturer's recommendation.Gene expression analysis was also performed via Reverse Transcriptionquantitative PCR (RT-qPCR) using a Stratagene Mx3005 instrument and SYBRgreen I (Life Technologies). Gene expression was measured of the splicedXbp1s transcript, a primer set measuring all Xbp1 transcripts, Xbp1starget genes including Sec24d and general ER stress response markersHspa5 (BiP) and Ddit3 (CHOP). These data indicate that Compound 3potently suppresses IRE1a-mediated XBP1 splicing in vivo after low-doseintraperitoneal injection.

Example 10: Inhibition of IRE1a Signaling in Cell Types within the TumorMicroenvironment

A syngeneic mouse model for metastatic, orthotopic ovarian cancer wasused to analyze the in vivo effects of compounds described herein. Assayconditions were similar to those described in Example 11, administeringcompound 3 for comparison against controls. As shown in the top panel ofFIG. 5 shows that mice with metastatic ovarian cancer were injected with11 mg/kg of Compound 3 or a vehicle. After 12 hours, the ascites weredrained and FACS was used to purify the cells into four populations:tumor cells, dendritic cells (DC), CD4+ T cells, and CD8+ T cells. Then,PCR and qPCR was used to quantify spliced Xbp1 transcripts and totalXbp1 transcripts. The bottom panel of FIG. 5 shows that the splicingratio of XBP1, calculated as the amount of spliced Xbp1 transcriptsdivided by the total Xbp1 transcripts, in the different cell types ofmice treated with Compound 3 was markedly reduced compared to thevehicle-treated mice. Compound 3 can therefore inhibit IRE1a-mediatedXBP1 splicing in vivo in tumor cells and key immune cell types foundwithin the tumor microenvironment.

Example 11: Xbp1 Activation in ID8 Mouse Model

A syngeneic mouse model for metastatic, orthotopic ovarian cancer isused to analyze the in vivo effects of compounds described herein. In afirst analysis, IRE1a/XBP1 activation is assessed in the ID8 mouse modelfor ovarian cancer.

Parental ID8 or aggressive ID8-Defb29/Vegf-A intraperitoneal ovariantumors are generated. About 1-2×10⁶ tumor cells are injected into wildtype female C57BL/6 mice. After 3 weeks, a first group of 3-5 tumorbearing mice (parental ID8 and ID8-Defb29/Vegf-A mice) and tumor-freenaïve mice are injected intraperitoneally with a compound from Table 1.Additional groups of 3-5 tumor bearing mice and naïve mice are injectedwith vehicle (PBS) as a control. Tumors are resected and ascites drainedfrom the mice 12-24 hours after the injection for analyzing IRE1apathway activation in the tumor microenvironment.

Fluorescently activated cell sorting (FACS) is then performed to purifycells from the tumors and ascites. Tumor dendritic cells (tDCs)(CD45⁺CD11c⁺CD11b⁺MHC-II⁺CD8α^(low)), tumor cells (CD45-SSC^(hi)), CD4+T cells (CD45⁺CD3⁺CD4⁺) and CD8+ T cells (CD45⁺CD3⁺CD4⁺) are isolatedfrom tumors and ascites of parental ID8 mice and ID8-Defb29/Vegf-A mice.Control splenic dendritic cells (sDCs) (CD45⁺CD11c⁺CD1 b⁺MHC-II⁺CD8α⁻)or splenic T cells (CD45⁺CD3⁺CD4⁺ or CD45⁺CD3⁺CD8⁺) are isolated fromspleens of naïve mice or ID8 mice and ID8-Defb29/Vegf-A mice. Duringsorting, viable cells are identified using the LIVE/DEAD Fixable YellowDead Cell Stain Kit (Life Technologies).

Total Xbp1 mRNA expression and spliced Xbp1 (Xbp1s) are quantified insDCs and T cells from naïve mice, sDCs and T cells from parental ID8mice and ID8-Defb29/Vegf-A mice, and tDCs, tumor cells, andtumor-infiltrating T cells from parental ID8 mice and ID8-Defb29/Vegf-Amice administered either vehicle or a compound from Table 1. Briefly,RNA from sorted cells are isolated using the Trizol reagent. 0.1-1 ug ofRNA are used to generate cDNA using the High Capacity cDNA ReverseTranscription Kit (Life Technologies). Mouse Xbp1 splicing assays areperformed using conventional Reverse Transcription PCR (RT-PCR) andprimers shown in Table 8. Gene expression analysis is also performed viaReverse Transcription quantitative PCR (RT-qPCR) using a StratageneMx3005 instrument and SYBR green I (Life Technologies). Gene expressionis measured of Xbp1 target genes including ERdj4, Sec24d, and Sec61a1and general ER stress response markers Hspa5 (BiP) and Ddit3 (CHOP).Murine Xbp1s transcript expression is analyzed using a primer that spansthe splicing junction site.

TABLE 8 SEQ ID Species Gene Oligo name Sequence 5′-3′ NO Purpose MouseXbp1 Xbp1-SA-F ACACGTTTGGGAATGGACAC Splicing Xbp1-SA-FCCATGGGAAGATGTTCTGGG Assay Mouse Actb actb1083 CTCAGGAGGAGCAATGATCTTRT-qPCR GAT actb987 TACCACCATGTACCCAGGCA Mouse Xbp1 Xbp1.total-FGACAGAGAGTCAAACTAACGT RT-qPCR GG Xbp1.total-R GTCCAGCAGGCAAGAAGGT MouseXbp1s XBPsA406F AAGAACACGCTTGGGAATGG RT-qPCR XBPsAa518RCTGCACCTGCTGCGGAC Mouse Xbp1 XBP1WT205-F CCTGAGCCCGGAGGAGAA RT-qPCR(exon 2) XBP1WT272-R CTCGAGCAGTCTGCGCTG Mouse Dnajb9/Erdj4 ERdj4-FTAAAAGCCCTGATGCTGAAGC RT-qPCR ERdj4-R TCCGACTATTGGCATCCGA Mouse Sec61a1Sec61a1-F CTATTTCCAGGGCTTCCGAGT RT-qPCR Sec61a1-R AGGTGTTGTACTGGCCTCGGTMouse Edem1 EDEM-F AAGCCCTCTGGAACTTGCG RT-qPCR EDEM-RAACCCAATGGCCTGTCTGG Mouse Hspa5/BiP Grp78-F TCATCGGACGCACTTGGAA RT-qPCRGrp78-R CAACCACCTTGAATGGCAAGA Mouse Ddit3/CHOP CHOP-FGTCCCTAGCTTGGCTGACAGA RT-qPCR CHOP-R TGGAGAGCGAGGGCTTTG Mouse Agpat6Agpat6-F AGCTTGATTGTCAACCTCCTG RT-qPCR

Protein analysis of XBP1S is performed by Western blot or intracellularflow cytometric analysis of sDCs and T cells from naïve mice, sDCs and Tcells from parental ID8 mice and ID8-Defb29/Vegf-A mice, and tDCs, tumorcells and tumor-infiltrating T cells from parental ID8 mice andID8-Defb29/Vegf-A mice administered either vehicle or a compound fromTable 1. Briefly, for Western blotting 5×10⁶ sDCs, tumor cells, T cells,or tDCs are washed twice in 1× cold PBS and nuclear proteins arepurified using the Nuclear Extraction Kit (Life Technologies). Proteinsare quantified using the BCA method (Pierce) and 15-20 ug of nuclearproteins are separated via SDS-PAGE and are transferred ontonitrocellulose membranes. Anti-mouse XBP1s (GL Biochem) is raised inrabbit using a peptide corresponding to the XBP1s C-terminus, and isused at a 1:500 dilution for immunoblotting. Goat anti-mouse Lamin B(Santa Cruz) is used at 1:2000. HRP-conjugated secondary antibodies torabbit and mouse (Santa Cruz) are used at a 1:2000 dilution. SuperSignalWest Femto (Pierce) is used as Chemiluminescent Substrate and blots areimaged using a FluorChemE instrument (ProteinSimple). For intracellularflow cytometry of XBP1s protein, 1-2 million splenocytes or dissociatedcells from solid tumors or ascites are washed in cold PBS and stainedwith the Ghost Dye 510 fixable viability dye diluted 1:1000 in PBS for30 minutes on ice. The staining reaction is quenched with 2 mL of FACSbuffer (PBS with 2% fetal bovine serum and 1 mM EDTA), cells pelleted bycentrifugation at 300×g for 5 minutes, and then surface stained withantibodies directed at key lineage defining markers such asCD45/CD3/CD4/CD8 (for T cells) or CD45/CD11c/MHC-II (for DCs) for 30minutes in FACS buffer on ice. Cells are washed twice with FACS bufferand then fixed and permeabilized for 30 minutes with the eBioscienceFoxP3 nuclear staining kit according to the manufacturer's protocol.Cells are washed twice with 1× permeabilization buffer, then Fcreceptors are blocked with Truestain FcX anti-mouse CD16/32 (Biolegend)for 15 minutes at room temperature. Finally, 5 microliters of XBP1santibody (clone Q3-695) or an equivalent amount of isotype controlantibody are added directly to cells and stained for 30 minutes at roomtemperature protected from light. Cells are washed twice with 1×permeabilization buffer and resuspended in FACS buffer, then analyzed ona flow cytometer such as the BD LSR II.

Example 12: Ovarian Cancer Progression

Tumor progression is measured in parental ID8 and aggressiveID8-Defb29/Vegf-A mice administered vehicle or a compound from Table 1.Similar to Example 1, parental ID8 or aggressive ID8-Defb29/Vegf-Aintraperitoneal ovarian tumors are generated. Briefly, 1-2×10⁶ tumorcells are injected into wild type C57BL/6 mice. After 2 weeks, a firstgroup of 8-10 tumor bearing mice (parental ID8 and ID8-Defb29/Vegf-Amice) and a separate group of naïve mice are injected intraperitoneallyonce per day with a compound from Table 1. Additional groups of tumorbearing mice and naïve mice are injected with PBS as a control. Incombination therapy studies, additional groups of mice are injectedevery other day with 200 ug isotype control antibody or blockingantibodies against CTLA-4 or PD-1. A final group of mice receives acombination therapy consisting of compound from Table 1 and 200 ugcheckpoint blocking antibody directed against either CTLA-4 or PD-1.

Tumor size, tumor volume, number of tumor masses as well as spleen sizeare then measured from vehicle or compound treated naïve mice, parentalID8 mice, and aggressive ID8-Defb29/Vegf-A mice. Naive mice aremonitored weekly for signs of morbidity or mortality from compoundtreatment. Malignant ascites accumulation is measured weekly as thepercentage of body weight gain, and animals are euthanized once theyreach 40% body weight gain. Survival of mice bearing parental ID8 tumorsor aggressive ID8-Defb29/Vegf-A tumors that are treated with vehicle ora compound from Table 1 is calculated as the number of days required toreach 40% weight gain since the tumor cells are originally injected.Compounds listed in Table 1 are assessed for reduction intumor-associated weight gain compared with vehicle control-treatedanimals.

Example 13: Lipid Analysis and Transcriptional Profiling

Lipid peroxidation byproducts are measured in mice described in Examples1-2. Intracellular lipid content is evaluated via flow cytometry using4,4-Difluoro1,3,5,7,8-Pentamethyl-4-Bora-3a,4a-Diaza-s-Indacene (BODIPY493/503; Life Technologies). Briefly, 5×10⁶ splenic cells or dendriticcells from naïve mice, parental ID8 mice, and aggressiveID8-Defb29/Vegf-A mice that are administered vehicle or a compound fromTable 1 are stained for surface markers using antibodies that do notoverlap with BODIPY 493/503, namely CD1 Ic-APC, CD45-APC-Cy7, andCD11b-Pacific Blue, followed by staining with 500 mL of BODIPY 493/503at 0.5 mg/mL in PBS for 15 minutes at room temperature in the dark.BODIPY 493/503 staining is then detected in the PE or FITC channel.Lipid analysis is also performed using electron microscopy analysis andmass spectrometry. In addition to lipid content, intracellular reactiveoxygen species (ROS) and 4-HNE adducts are measured with2′,7′-dichlorofluorescin diacetate (DCFDA) and a competitive ELISA assay(Cell Biolabs), respectively.

Transcriptional profiling is performed in naïve mice, parental ID8 mice,and aggressive ID8-Defb29/Vegf-A mice that are treated with vehicle or acompound from Table 1. Gene expression of genes that are involved inunfolded protein response (UPR)/endoplasmic reticulum (ER) stress andgenes involved in lipid metabolism are measured in tDCs purified byFACS. These include but are not limited to Sec24d, Sec61a1, P4hb, Fasn,Agpat4, and Agpat6. XBP1 pathway activation and key effector functionsare also measured by quantitative PCR in tumor-infiltrating lymphocytespurified by FACS. Compounds listed in Table 1 are assessed for reductionin XBP1s target gene expression and BODIPY 493/503 fluorescence intumor-associated DCs.

Example 14: T Cell Activation

T cell activation is determined in ovarian cancer bearing mice followingadministration of compounds described herein. In vivo antigenpresentation experiments are performed in wild-type C57BL/6 female micebearing parental ID8 or ID8-Defb29/Vegf-A ovarian tumors. After threeweeks, naïve mice, parental ID8 mice, or ID8-Defb29/Vegf-A mice areintraperitoneally injected with 0.6 mg of full length endotoxin-freeovalbumin (OVA) (SIGMA, grade VII). Mice are then injected with vehicleor a compound from Table 1 3 hours later. After 18 hours, mice receiveintraperitoneally 2×10⁶ CFSE-labeled T cells negatively purified fromOT-1 transgenic mice. Peritoneal wash samples (10 mL) are collectedafter 72 hours and analyzed for CFSE dilution via FACS to calculatenumber of T cell divisions. Data are analyzed using FlowJo version 9 or10.

In vitro antigen presentation experiments are performed with isolatedtDCs from wild-type C57BL/6 female mice bearing parental ID8 orID8-Defb29/Vegf-A ovarian tumors. After 3-4 weeks of tumor burden, tDCsare purified by FACS from the peritoneal cavity of naïve mice, parentalID8 mice, or ID8-Defb29/Vegf-A, and are pulsed with full-lengthendotoxin-free ovalbumin protein (Sigma, grade VII) in cRPMI containing25% cell-free ovarian cancer ascites supernatants overnight at 37° C.Antigen-loaded tDCs are then washed twice with cRPMI and co-culturedwith CFSE-labeled OT-I CD8+ T cells immunopurified from OT-1 mice at a1:10 (DC to T cell) ratio. After 3-5 days, cultures analyzed for CFSEdilution via FACS to calculate number of T cell divisions. Data areanalyzed using FlowJo version 9 or 10. Isolated tDCs from animalstreated with a compound from Table 1 are assessed for enhancement of Tcell proliferation relative to tDCs isolated from vehicle-treatedcontrols.

Example 15: Anti-Tumor Immunity

Effects of test compounds in inducing anti-tumor immunity are analyzed.Mice are intraperitoneally injected with ID8-Defb29/Vegf-A ovariancancer cells and are treated with a compound from Table 1 (n=3-5/group)or vehicle daily starting at day 14 after tumor challenge. After 1-2weeks of daily treatment, peritoneal lavage samples are analyzed for thenumber of metastatic cancer cells and tumor ascites accumulation in theperitoneal cavity.

The capacity for T cells to respond to tumor antigens is also measured.Freshly isolated ascites cells are cultured in 96-well flat bottomplates for 6 hours in the presence of PMA, lonomycin and Brefeldin A toinduce cytokine translation and retention within the secretory pathway.After this stimulation period, the cells are washed twice with FACSbuffer (PBS+2% FBS and 1 mM EDTA) and stained for 30 minutes with GhostDye 510 Violet (Tonbo Biosciences) in PBS on ice according to themanufacturer's protocol. Cells are then washed twice more with FACSbuffer and then stained with antibodies directed against CD45, CD3, CD4,CD8, and CD44 on ice for 30 minutes. Fc receptors are also blocked atthis time with the TrueStain FcX Antibody (anti-CD16/32, Biolegend).After this staining period, cells are washed twice more with FACSbuffer, resuspended in 1× Fix/Perm reagent (eBioscienceFoxp3/Transcription Factor Staining Buffer Set), mixed well by pipetting2-3 times and incubated for 30 minutes at room temperature protectedfrom light. Cells are then washed twice with 1× permeabilization bufferand stained at room temperature with antibodies directed against murineFc receptor CD16/32 (Fc Block), IFN-gamma and Granzyme-B for 30 minutes.After this incubation period, cells are washed once with 1×permeabilization buffer, once with FACS buffer, and resuspended in FACSbuffer for analysis by flow cytometry. Data are analyzed using FlowJoversion 9 or 10.

Total splenic T cells or Ficoll-enriched leukocytes (2-3×10⁵) fromperitoneal wash samples are obtained 4 days after the last treatment(day 27) and are cocultured in 10% FBS RPMI with 2-3×10⁴ bonemarrow-derived DCs that are pulsed overnight with irradiatedID8-Defb29/Vegf-A ovarian cancer cells. Supernatants are collected after48-72 hours of stimulation. IFN-γ and Granzyme B secretion is determinedby ELISA using the Ready-SET-Go Kit (eBioscience). Tumor-resident Tcells from animals treated with a compound from Table 1 are assessed forincreased IFN-γ and Granzyme B production relative to T cells isolatedfrom vehicle-treated controls.

Example 16: IC₅₀ Measurements for hERG Potassium Ion Channel

Blockade of the cardiac ion channel coded by the hERG gene can lead tocardiac arrhythmia. Many small compounds have been found to bind to thehERG gene leading to problems in the QT response. To determine theviability of the compounds disclosed herein as pharmacological agentsthat would not affect the hERG channel blockade, a standard automatedplanar clamp method was employed to determine the IC₅₀ for various testcompounds on their inhibition of the channel. An electrophysiologicalassay was prepared to measure the electric current passing through thehERG channel expressed in a stable CHO cell line by applying the planarclamp method. This assay was performed using the automated QPatchplatform (Sophion, Denmark) which allows fast and accurateelectrophysiological characterization of the hERG ion channel and thedetermination of IC₅₀ values for the test compounds, as shown in Table9. The significant separation (100-1000×) between effects againstIRE1a-mediated XBP1 splicing in 293T cells and the effect on hERGchannels suggest that there is a good safety margin for targeting IRE1a.

TABLE 9 Compound Ref. No. Mean IC₅₀  3; Formic Acid B 16; Formic Acid B24; Formic Acid C 37; HCl      B 69; Formic Acid B Note: hERG channelblockade Mean IC₅₀ data are designated within the following ranges:A: >50 uM; B: >10 uM to ≤50 uM, C: >1 uM to ≤10 uM; and D: ≤1 uM.

Example 17: Pharmacokinetic Studies

Compounds are tested in a pharmacokinetic (“PK”) study to determine thehalf-life (T_(1/2)) in mice. A compound from Table 1 is dissolved in avehicle to make a test antibiotic composition. The vehicle might be, forexample, a water or a 25% PEG400 in saline solution Administration toeach mouse is performed via intravenous (IV) cannulation of the tailvein. Blood is collected over K2-EDTA anticoagulant from thesubmandibular or saphenous vein at predetermined time points. Followingcollection, the blood samples are stored at −70° C. until analysis byLC-MS and comparison to a standard calibration curve results in theT_(1/2) for each compound.

Alternatively, on study day, the animals (fasted) usually receive acompound from Table 1 (typically 10 or 30 mg/kg) by IP injection(typically 10 mL/kg). The IP dose is typically delivered via a bolusinto the IP space for mice. All dosages are expressed as target dose inmg free base/acid equivalent/kg; actual doses are calculated for eachindividual animal and are recorded. The plasma samples are thencollected as above and plasma levels determined.

Example 18: Protein Binding—Plasma Protein Binding Assay-HTD Method

The plasma protein binding is determined according to the followingsteps. Frozen plasma or freshly prepared plasma from various subjectsare used as test matrix. They are purchased from commercial vendors orprepared in house from animals. Warfarin is used as a positive control.Other control compound(s) may be used according to specific requirement.One or more compounds from Table 1 are spiked into blank matrix at thefinal concentration of 2 μM (or other test concentrations based onspecific requirement). Final organic solvent concentration is <1%. Ifplasma samples are collected from in-life studies, they are used as testmatrix without spiking compounds. An appropriate volume of spiked plasmasolution is removed before incubation for recovery calculation. Analiquot (e.g., 150 uL) of matrix sample is added to one side of thechamber (donor chamber) in a 96-well equilibrium dialyzer plate (HTDdialysis device) and an equal volume of dialysis buffer is added to theother side of the chamber (receiver chamber). Triplicate incubations areperformed (or other replicate number according to specific requirement).The dialyzer plate is placed into a humidified incubator with 5% CO₂ andincubated at 37° C. for 4 to 6 hours. After incubation, samples aretaken from the donor chamber as well as the receiver chamber. The plasmasample is matched with an appropriate volume of blank buffer; and buffersamples are matched with an appropriate volume of blank plasma. Thematrix-matched samples are quenched with stop solution containinginternal standard. Samples are analyzed by LC/MS/MS. Test compoundconcentrations in donor and receiver samples are expressed as peak arearatios of analyte/internal standard. If a quantitative analysis isneeded, a set of calibration curve and quality controls could beincluded.

Example 19: Inhibition of Triple Negative Breast Cancer

XBP1 is known to binds directly to HIFla in triple negative breastcancer, and this cooperative binding enhances the upregulation ofHIF1a-dependent downstream target genes. Compounds in Table 1 arescreened for impact on XBP1 protein level, thereby removing a keybinding partner for HIF1a and reducing expression of HIFla-dependenttarget genes such as VEGFA, PDK1, GLUT1, and JMJD1A. Specifically, humantriple-negative breast cancer cell lines are treated with vehiclecontrol or a compound shown in Table 1, then cultured under hypoxia(0.1% O₂) for 24 hours. Cells are then lysed with RLT buffer, RNAextracted with the RNeasy 96 kit (Qiagen) and complementary DNAgenerated from the pure RNA. Semi-quantitative PCR and quantitative PCRare then used to quantify spliced Xbp1 transcripts, total Xbp1transcripts, target genes regulated by XBP1s (e.g. SEC61A1, P4HB, EDEM1,AND SEC24D) and target genes regulated by HIFla (e.g. VEGFA, PDK1,GLUT1, and JMJD1A). The splicing ratio of XBP1 is calculated bydetermining the amount of spliced Xbp1 transcripts divided by the totalnumber of spliced and unspliced Xbp1 transcripts, an indicator forcompounds that inhibit critical intracellular signaling required forTNBC tumor-initiating cell function and metastatic capacity. Compoundsshown in Table 1 are assessed for downregulation of XBP1s, XBP1 splicingration, XBP1s-dependent target gene expression, and HIFla target geneexpression relative to DMSO control-treated samples.

Example 20: Soft Agar Colony Formation Assay

One hundred thousand breast cancer cells are mixed 4:1 (v/v) with 2.0%agarose in growth medium containing vehicle control or a compound listedin Table 1 for a final concentration of 0.4% agarose. The cell mixtureis plated on top of a solidified layer of 0.8% agarose in growth medium.Cells are fed every 6-7 days with growth medium containing 0.4% agaroseand vehicle control or a compound from Table 1, matching the initialplating conditions. The number of colonies are counted after 20 days,with the number of colonies visible at the end of the growth period toidentify colonies with reduced growth.

Example 21: Inhibition of Metastatic Breast Cancer

Mice with established metastatic breast cancer are separately injectedwith each of the compounds in Table 1. After 12 hours, the tumors areexcised, mechanically separated, and enzymatically digested to singlecell suspensions. Flow-assisted cell sorting is then used to purify fourpopulations of cells: tumor cells, dendritic cells (DC), CD4+ T cells,and CD8+ T cells. The cells are sorted directly into RLT buffer forinstant cell lysis and RNase deactivation. Then, cellular RNA ispurified with the RNeasy 96 kit (Qiagen), and complementary DNAgenerated from the pure RNA. Semi-quantitative PCR and quantitative PCRare then used to quantify spliced Xbp1 transcripts, total Xbp1transcripts, and target genes regulated by XBP1 s such as SEC61A1, P4HB,EDEM1, AND SEC24D. The splicing ratio of XBP1 is calculated bydetermining the amount of spliced Xbp1 transcripts divided by the totalnumber of spliced and unspliced Xbp1 transcripts, an indicator forcompounds that inhibit metastatic breast cancer. Compounds shown inTable 1 are assessed for reduction in XBP1s transcripts, XBP1 splicingand downstream XBP1s target genes relative to vehicle control-treatedmice.

Example 22: Inhibition of Lung Cancer

Mice with established primary or metastatic lung cancer are separatelyinjected with each of the compounds in Table 1. After 12 hours, thetumors are excised, mechanically separated, and enzymatically digestedto single cell suspensions. Flow-assisted cell sorting is then used topurify four populations of cells: tumor cells, dendritic cells (DC),CD4+ T cells, and CD8+ T cells. The cells are sorted directly into RLTbuffer for instant cell lysis and RNase deactivation. Then, cellular RNAis purified with the RNeasy 96 kit (Qiagen), and complementary DNAgenerated from the pure RNA. Semi-quantitative PCR and quantitative PCRare then used to quantify spliced Xbp1 transcripts, total Xbp1transcripts, and target genes regulated by XBP1s such as SEC61A1, P4HB,EDEM1, AND SEC24D. The splicing ratio of XBP1 is calculated bydetermining the amount of spliced Xbp1 transcripts divided by the totalnumber of spliced and unspliced Xbp1 transcripts, an indicator forcompounds that inhibit primary or metastatic lung cancer. Compoundsshown in Table 1 are assessed for reduction in XBP1s transcriptsrelative to vehicle control-treated mice.

Example 23: Inhibition of Bladder Cancer

Mice with established primary or metastatic bladder cancer areseparately injected with each of the compounds in Table 1. After 12hours, the tumors are excised, mechanically separated, and enzymaticallydigested to single cell suspensions. Flow-assisted cell sorting is thenused to purify four populations of cells: tumor cells, dendritic cells(DC), CD4+ T cells, and CD8+ T cells. The cells are sorted directly intoRLT buffer for instant cell lysis and RNase deactivation. Then, cellularRNA is purified with the RNeasy 96 kit (Qiagen), and complementary DNAgenerated from the pure RNA. Semi-quantitative PCR and quantitative PCRare then used to quantify spliced Xbp1 transcripts, total Xbp1transcripts, and target genes regulated by XBP1s such as SEC61A1, P4HB,EDEM1, AND SEC24D. The splicing ratio of XBP1 is calculated bydetermining the amount of spliced Xbp1 transcripts divided by the totalnumber of spliced and unspliced Xbp1 transcripts, an indicator forcompounds from that inhibit primary or metastatic bladder cancer.Compounds shown in Table 1 are assessed for reduction in XBP1stranscripts, XBP1 splicing and downstream XBP1s target genes relative tovehicle control-treated mice.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

SEQUENCE LISTING SEQ ID NO: 1MPARRLLLLLTLLLPGLGIFGSTSTVTLPETLLFVSTLDGSLHAVSKRTGSIKWTLKEDPVLQVPTHVEEPAFLPDPNDGSLYTLGSKNNEGLTKLPFTIPELVQASPCRSSDGILYMGKKQDIWYVIDLLTGEKQQTLSSAFADSLCPSTSLLYLGRTEYTITMYDTKTRELRWNATYFDYAASLPEDDVDYKMSHFVSNGDGLVVTVDSESGDVLWIQNYASPVVAFYVWQREGLRKVMHINVAVETLRYLTFMSGEVGRITKWKYPFPKETEAKSKLTPTLYVGKYSTSLYASPSMVHEGVAVVPRGSTLPLLEGPQTDGVTIGDKGECVITPSTDVKFDPGLKSKNKLNYLRNYWLLIGHHETPLSASTKMLERFPNNLPKHRENVIPADSEKKSFEEVINLVDQTSENAPTTVSRDVEEKPAHAPARPEAPVDSMLKDMATIILSTFLLIGWVAFIITYPLSMHQQQQLQHQQFQKELEKIQLLQQQQQQLPFHPPGDTAQDGELLDTSGPYSESSGTSSPSTSPRASNHSLCSGSSASKAGSSPSLEQDDGDEETSVVIVGKISFCPKDVLGHGAEGTIVYRGMFDNRDVAVKRILPECFSFADREVQLLRESDEHPNVIRYFCTEKDRQFQYIAIELCAATLQEYVEQKDFAHLGLEPITLLQQTTSGLAHLHSLNIVHRDLKPHNILISMPNAHGKIKAMISDFGLCKKLAVGRHSFSRRSGVPGTEGWIAPEMLSEDCKENPTYTVDIFSAGCVFYYVISEGSHPFGKSLQRQANILLGACSLDCLHPEKHEDVIARELIEKMIAMDPQKRPSAKHVLKHPFFWSLEKQLQFFQDVSDRIEKESLDGPIVKQLERGGRAVVKMDWRENITVPLQTDLRKFRTYKGGSVRDLLRAMRNKKHHYRELPAEVRETLGSLPDDFVCYFTSRFPHLLAHTYRAMELCSHERLFQPYYFHEPPEPQPPVTPDAL SEQ ID NO: 2 CAUGUCCGCAGCACAUG SEQ ID NO: 3CAUGUCCCCAGCACAUG

1. A compound of Formula (I), or a pharmaceutically acceptable salt, orsolvate thereof:

wherein,

is a substituted C₃-C₁₀ cycloalkyl that is substituted with 1-3R¹ and0-3R²; each R¹ is independently —OR⁶, —SR⁶, —S(═O)R⁷, —S(═O)₂R⁷, or—N(R⁶)₂; each R² is independently H, halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁹,—S(═O)₂R⁹, —S(═O)₂N(R⁸)₂, —NR⁸S(═O)₂R⁹, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R⁸,—CO₂R⁹, —N(R⁸)₂, —OC(═O)N(R⁸)₂, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄fluoroalkyl,optionally substituted C₁-C₄heteroalkyl, optionally substitutedC₃-C₆cycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; each R⁶ is independently H, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄heteroalkyl, optionallysubstituted C₁-C₄fluoroalkyl, —X-optionally substituted C₁-C₄alkyl,—X-optionally substituted C₁-C₄heteroalkyl, —X-optionally substitutedC₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl, optionallysubstituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl; or two R⁶ are taken together with theN atom to which they are attached to form an optionally substitutedheterocycle; X is —(C═O)—; each R⁷ is independently optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄heteroalkyl,optionally substituted C₁-C₄fluoroalkyl, optionally substitutedC₃-C₆cycloalkyl, optionally substituted C₂-C₁₀heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl; eachR⁸ is independently H, optionally substituted C₁-C₄alkyl, optionallysubstituted C₁-C₄heteroalkyl, optionally substituted C₁-C₄fluoroalkyl,optionally substituted C₃-C₆cycloalkyl, optionally substitutedC₂-C₁₀heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; or two R⁸ are taken together with the N atom towhich they are attached to form an optionally substituted heterocycle;each R⁹ is independently optionally substituted C₁-C₄alkyl, optionallysubstituted C₁-C₄heteroalkyl, or optionally substitutedC₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl, optionallysubstituted C₂-C₁₀heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl; A² is N or CR^(A); R^(A), R^(A1),R^(A2), and R^(A3) are each independently H, halogen, optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄fluoroalkyl,optionally substituted aryl, or —OR¹⁰; R¹⁰ is independently H,optionally substituted C₁-C₄alkyl, optionally substitutedC₁-C₄fluoroalkyl, optionally substituted C₁-C₄heteroalkyl, optionallysubstituted C₃-C₆cycloalkyl, optionally substitutedC₂-C₁₀heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; ring A is a monocyclic carbocycle or amonocyclic heterocycle; each R³ is independently H, halogen, —CN, —OR¹¹,—SR¹¹, —N(R¹¹)₂, optionally substituted C₁-C₄alkyl, optionallysubstituted C₁-C₄fluoroalkyl, optionally substituted C₁-C₄heteroalkyl,optionally substituted C₃-C₆cycloalkyl, optionally substitutedC₂-C₁₀heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; each R¹¹ is independently H, optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄fluoroalkyl,optionally substituted C₁-C₄heteroalkyl, optionally substitutedC₃-C₆cycloalkyl, optionally substituted C₂-C₁₀heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl; n is0, 1, 2, 3, or 4; R⁴ and R⁵ are each independently H, halogen, —CN,—OR¹², —SR¹², —N(R¹²)₂, optionally substituted C₁-C₄alkyl, optionallysubstituted C₁-C₄fluoroalkyl, optionally substituted C₁-C₄heteroalkyl,optionally substituted C₃-C₆cycloalkyl, optionally substitutedC₂-C₁₀heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and R¹² is independently H, optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄fluoroalkyl,optionally substituted C₁-C₄heteroalkyl, optionally substitutedC₃-C₆cycloalkyl, optionally substituted C₂-C₁₀heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl. 2.(canceled)
 3. The compound of claim 1, or a pharmaceutically acceptablesalt, or solvate thereof, wherein

and q is 0, 1, 2, or
 3. 4. (canceled)
 5. The compound of claim 3, or apharmaceutically acceptable salt, or solvate thereof, wherein

and q is 0, 1, 2, or
 3. 6. (canceled)
 7. The compound of claim 5, or apharmaceutically acceptable salt, or solvate thereof, wherein each R⁶ isindependently H, optionally substituted C₁-C₄alkyl, optionallysubstituted C₁-C₄heteroalkyl, optionally substituted C₁-C₄fluoroalkyl,—X-optionally substituted C₁-C₄alkyl, —X-optionally substitutedC₁-C₄heteroalkyl, or —X-optionally substituted C₁-C₄fluoroalkyl; andeach R² is independently H, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄heteroalkyl, or optionally substitutedC₁-C₄fluoroalkyl.
 8. The compound of claim 7, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein each R⁶ is independently H.9. (canceled)
 10. The compound of claim 5, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein

R⁶ is H, optionally substituted C₁-C₄alkyl, optionally substitutedC₁-C₄heteroalkyl, optionally substituted C₁-C₄fluoroalkyl, —X-optionallysubstituted C₁-C₄alkyl, —X-optionally substituted C₁-C₄heteroalkyl, or—X-optionally substituted C₁-C₄fluoroalkyl; q is 0 or 1; and R² is H,optionally substituted C₁-C₄alkyl, optionally substitutedC₁-C₄heteroalkyl, or optionally substituted C₁-C₄fluoroalkyl.
 11. Thecompound of claim 10, or a pharmaceutically acceptable salt, or solvatewherein R⁶ is optionally substituted C₁-C₄alkyl, optionally substitutedC₁-C₄heteroalkyl, optionally substituted C₁-C₄fluoroalkyl, —X-optionallysubstituted C₁-C₄alkyl, —X-optionally substituted C₁-C₄heteroalkyl, or—X-optionally substituted C₁-C₄fluoroalkyl.
 12. The compound of claim 1,or a pharmaceutically acceptable salt, or solvate thereof, wherein A² isN. 13.-16. (canceled)
 17. The compound of claim 1, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein R^(A1) is H.
 18. Thecompound of claim 1, or a pharmaceutically acceptable salt, or solvatethereof, wherein R^(A2) is H, optionally substituted C₁-C₄alkyl, oroptionally substituted C₁-C₄fluoroalkyl. 19.-20. (canceled)
 21. Thecompound of claim 1, or a pharmaceutically acceptable salt, or solvatethereof, wherein R^(A3) is H, halogen, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄fluoroalkyl, or —OR¹⁰.
 22. Thecompound of claim 21, or a pharmaceutically acceptable salt, or solvatethereof, wherein R^(A3) is optionally substituted C₁-C₄alkyl. 23.-26.(canceled)
 27. The compound of claim 1, or a pharmaceutically acceptablesalt, or solvate thereof, wherein:

28.-30. (canceled)
 31. The compound of claim 1, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein:


32. The compound of claim 31, or a pharmaceutically acceptable salt, orsolvate thereof, wherein:

33.-39. (canceled)
 40. The compound of claim 1, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein each R³ is independently H,halogen, —CN, —OR¹¹, —SR¹¹, optionally substituted C₁-C₄alkyl, oroptionally substituted C₁-C₄fluoroalkyl; and n is 1, 2, or
 3. 41. Thecompound of claim 40, or a pharmaceutically acceptable salt, or solvatethereof, wherein R³ is optionally substituted C₁-C₄alkyl. 42.-48.(canceled)
 49. The compound of claim 1, or a pharmaceutically acceptablesalt, or solvate thereof, wherein R⁴ is halogen or optionallysubstituted C₁-C₄alkyl. 50.-57. (canceled)
 58. The compound of claim 1,or a pharmaceutically acceptable salt, or solvate thereof, wherein R⁵ isH. 59.-94. (canceled)
 95. The compound of claim 1, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein the compound has thestructure of formula (Id)

and R^(A3) is optionally substituted C₁-C₄ alkyl.
 96. The compound ofclaim 95, or a pharmaceutically acceptable salt, or solvate thereof,wherein the compound has the structure of formula (Ie)


97. The compound of claim 95, or a pharmaceutically acceptable salt, orsolvate thereof, wherein the compound has the structure of formula (If)


98. (canceled)
 99. The compound of claim 97, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein R⁴ and R⁵ are eachindependently H, halogen, —CN, —OR¹², —SR¹², —N(R¹²)₂, optionallysubstituted C₁-C₄alkyl, or optionally substituted C₁-C₄fluoroalkyl. 100.The compound of claim 1, or a pharmaceutically acceptable salt, orsolvate thereof, wherein the compound is a compound selected from:N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3-methylphenyl)-2-chlorobenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)-2-chlorobenzenesulfonamide;N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methylpyridin-2-yl)-2-chlorobenzenesulfonamide;N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-4-methylpyridin-2-yl)-2-chlorobenzenesulfonamide;N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)-2-(trifluoromethyl)benzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)-2-(trifluoromethoxy)benzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)-2,5-dichlorobenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)-2-fluorobenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3-methylphenyl)-3-chlorobenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)-4-chlorobenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)-2-methoxybenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-(trifluoromethyl)phenyl)-2-chlorobenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)benzenesulfonamide;N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-2-chlorobenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-chlorophenyl)-2-chlorobenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)phenyl)-2-chlorobenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methoxyphenyl)-2-chlorobenzenesulfonamide;N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methylpyridin-3-yl)-2-chlorobenzenesulfonamide;N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluoro-5-methylphenyl)-2-chlorobenzenesulfonamide;or N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2,3-dimethylphenyl)-2-chlorobenzenesulfonamide.101.-143. (canceled)
 144. A pharmaceutical composition comprising: acompound according to claim 1, or a pharmaceutically acceptable salt orsolvate thereof; and one or more pharmaceutically acceptable excipients.145. (canceled)
 146. A method for treating or ameliorating the effectsof a disease associated with altered IRE1 signaling, the methodcomprising administering to a subject in need thereof a pharmaceuticalcomposition, wherein the pharmaceutical composition comprises a compoundof claim
 1. 147. The method of claim 146, wherein the disease is cancer.148. (canceled)
 149. The method of claim 147, wherein the cancer isovarian cancer, breast cancer, or triple negative breast cancer (TNBC).150.-154. (canceled)
 155. The compound of claim 1, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein:

and q is 0, 1, 2, or 3; each R⁶ is independently H, optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄heteroalkyl,optionally substituted C₁-C₄fluoroalkyl, —X-optionally substitutedC₁-C₄alkyl, —X-optionally substituted C₁-C₄heteroalkyl, or —X-optionallysubstituted C₁-C₄fluoroalkyl; each R² is independently H, optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄heteroalkyl, oroptionally substituted C₁-C₄fluoroalkyl; A² is N; R^(A1) is H; R^(A3) ismethyl, ethyl, propyl or butyl; R⁴ is —Cl, —Br, —F, or —I; R⁵ ishydrogen; R^(A2) is H; ring A is pyridinylene; n is 1, 2, or 3; and R³is methyl, ethyl, propyl, or butyl; or R³ is —OR¹¹ and R¹¹ is methyl,ethyl, propyl, or butyl; or R³ is —OR¹¹ and R¹¹ is CF₃ or —CH₂CF₃.